Category Archives: Colon Cancer or Colorectal cancer

angiogenesis, Anti-angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, Apoptotic, BAX, Bcl-2, bFGF, Breast cancer, c-Jun, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, chemotherapy support, Colon Cancer or Colorectal cancer, Cytostatic, Diarrhea or Constipation, ERK, Hair Loss, IAP, IL-10, IL-2, IL-6, IL-8, immunotolerance, JNK, Liver cancer, Lung cancer, Osteosarcoma, Pancreatic cancer, radiation support, RANK, Rectal cancer, Sarcoma, sIL-2R, TNF, tumor-inhibitory, VEGF, VEGF

Oxymatrine or Compound Matrine (Ku Shen)

Cancer: Sarcoma, pancreatic, breast, liver, lung, oral., rectal., stomach, leukemia, adenoid cystic carcinoma

Action: Anti-inflammatory, anti-proliferative, chemo-sensitizer, chemotherapy support, cytostatic, radiation support, anti-angiogenesis

Ingredients: ku shen (Sophora flavescens), bai tu ling (Heterosmilax chinensis).

TCM functions: Clearing Heat, inducing diuresis, cooling Blood, removing Toxin, dispersing lumps and relieving pain (Drug Information Reference in Chinese: See end, 2000-12).

Indications: Pain and bleeding caused by cancer.

Dosage and usage:

Intramuscular injection: 2-4 ml each time, twice daily; intravenous drip: 12 ml mixed in 200 ml NaCl injection, once daily. The total amount of 200 ml administration makes up a course of treatment. 2-3 consecutive courses can be applied.

Anti-cancer

Oxymatrine, isolated from the dried roots of Sophora flavescens (Aiton), has a long history of use in traditional Chinese medicine to treat inflammatory diseases and cancer. Kushen alkaloids (KS-As) and kushen flavonoids (KS-Fs) are well-characterized components in kushen. KS-As containing oxymatrine, matrine, and total alkaloids have been developed in China as anti-cancer drugs. More potent anti-tumor activities were identified in KS-Fs than in KS-As in vitro and in vivo (Sun et al., 2012). The four major alkaloids in compound Ku Shen injection are matrine, sophoridine, oxymatrine and oxysophocarpine (Qi, Zhang, & Zhang, 2013).

Sarcoma

When a high dose was used, the tumor-inhibitory rate of oxymatrine was 31.36%, and the vascular density of S180 sarcoma was lower than that in the control group and the expression of VEGF and bFGF was down-regulated. Oxymatrine hence has an inhibitory effect on S180 sarcoma and strong inhibitory effects on angiogenesis. Its mechanism may be associated with the down-regulating of VEGF and bFGF expression (Kong et al., 2003).

T Cell Leukemia

Matrine, a small molecule derived from the root of Sophora flavescens AIT was demonstrated to be effective in inducing T cell anergy in human T cell leukemia Jurkat cells.

The results showed that passage of the cells, and concentration and stimulation time of ionomycin on the cells could influence the ability of T cell anergy induction.

The cells exposed to matrine showed markedly decreased mRNA expression of interleukin-2, an indicator of T cell anergy. Pre-incubation with matrine or ionomycin could also shorten extracellular signal-regulated kinase (ERK) and suppress c-Jun NH(2)-terminal kinase (JNK) expression on the anergic Jurkat cells when the cells were stimulated with anti-OKT-3 plus anti-CD28 antibodies. Thus, matrine is a strong candidate for further investigation as a T cell immunotolerance inducer (Li et al., 2010).

Osteosarcoma

Results showed that treatment with oxymatrine resulted in a significant inhibition of cell proliferation and DNA synthesis in a dose-dependent manner, which has been attributed to apoptosis. Oxymatrine considerably inhibited the expression of Bcl-2 whilst increasing that of Bax.

Oxymatrine significantly suppressed tumor growth in female BALB/C nude mice bearing osteosarcoma MNNG/HOS xenograft tumors. In addition, no evidence of drug-related toxicity was identified in the treated animals by comparing the body weight increase and mortality (Zhang et al., 2013).

Pancreatic Cancer

Oxymatrine decreased the expression of angiogenesis-associated factors, including nuclear factor κB (NF-κB) and vascular endothelial growth factor (VEGF). Finally, the anti-proliferative and anti-angiogenic effects of oxymatrine on human pancreatic cancer were further confirmed in pancreatic cancer xenograft tumors in nude mice (Chen et al., 2013).

Furthermore, oxymatrine treatment led to the release of cytochrome c and activation of caspase-3 proteins. Oxymatrine can induce apoptotic cell death of human pancreatic cancer, which might be attributed to the regulation of Bcl-2 and IAP families, release of mitochondrial cytochrome c and activation of caspase-3 (Ling et al., 2011).

Rectal Carcinoma

Eighty-four patients diagnosed with rectal carcinoma at the People”s Hospital of Yichun city in Jiangxi province from September 2006 to September 2011, were randomly divided into two groups: therapeutic group and control group. The patients in the therapeutic group were treated with compound matrine and intensity modulated radiation therapy (IMRT) (30 Gy/10 f/2 W), while the patients in control group were treated with IMRT.

The clinical effect and survival rate in the therapeutic group were significantly higher (47.6%) than those in the control group (21.4%). All patients were divided by improvement, stability, and progression of disease in accordance with Karnofsky Performance Scale (KPS). According to the KPS, 16 patients had improvement, 17 stabilized and 9 had disease progress in the therapeutic group.

However, the control group had 12 improvements, 14 stabilized, and 16 disease progress. Quality of life in the therapeutic group was higher than that in the control group by rank sum test. The level of sIL-2R and IL-8 in the therapeutic group was lower on the first and 14th day, post radiation, when compared to the control group. However, there was no significant difference on the first day and 14th day, between both experimental groups post therapy, according to the student test. Compound matrine can decrease the side-effects of IMRT, significantly inhibit sIL-2R and IL-8 in peripheral blood from radiation, and can improve survival quality in patients with rectal cancer (Yin et al., 2013).

Gastric Cancer

Seventy-six cases of advanced gastric cancer were collected from June 2010 to November 2011, and randomly divided into either an experimental group or control group. Patients in the two groups were treated with matrine injection combined with SP regimen, or SP regimen alone, respectively. The effectiveness rate of the experimental group and control group was 57.5% and 52.8% respectively.

The treatment of advanced gastric cancer with matrine injection, combined with the SP regimen, can significantly improve levels of white blood cells and hemoglobin, liver function, incidence of diarrhea and constipation, and neurotoxicity, to improve the quality of life in patients with advanced gastric cancer (Xia, 2013).

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC-2) cells were cultured in vitro. MTT assay was used to measure the cell proliferative effect. Compound radix Sophorae flavescentis injection could inhibit the proliferation of ACC-2 cells in vitro, and the dosage effect relationship was significant (P < 0.01). Radix Sophorae flavescentis injection could enhance ACC-2 cells Caspase-3 protein expression (P < 0.05 or P < 0.01), in a dose-dependent manner. It also could effectively restrain human adenoid cystic carcinoma ACC-2 cells Caspases-3 protein expression, and induce apoptosis, inhibiting tumor cell proliferation (Shi & Hu, 2012).

Breast Cancer; Chemotherapy

A retrospective analysis of oncological data of 70 postoperative patients with breast cancer from January 2008 to August 2011 was performed. According to the treatment method, the patients were divided into a therapy group (n=35) or control group (n=35). Patients in the control group were treated with the taxotere, adriamycin and cyclophosphamide regimen (TAC). The therapy group was treated with a combination of TAC and sophora root injection. Improved quality of life and incidence of adverse events, before and after treatment, for 2 cycles (21 days for a cycle) were compared.

The improvement rate of total quality of life in the therapy group was higher than that of the control group (P < 0.05). The drop of white blood cells and platelets, gastrointestinal reaction, elevated SGPT, and the incidence of hair loss in the therapy group were lower than those of the control group (P < 0.05).

Sophora root injection combined with chemotherapy in treatment of breast cancer can enhance the effect of chemotherapy, reduce toxicity and side-effects, and improve quality of life (An, An, & Wu, 2012).

Lung cancer; Pleural Effusion

The therapeutic efficiency of Fufang Kushen Injection Liquid (FFKSIL), IL-2, α-IFN on lung cancer accompanied with malignancy pleural effusions, was observed.

One hundred and fifty patients with lung cancer, accompanied with pleural effusions, were randomly divided into treatment and control groups. The treatment group was divided into three groups: injected FFKSIL plus IL-2, FFKSIL plus α-tFN, and IL-2 plus α>-IFN, respectively. The control group was divided into three groups and injected FFKSIL, IL-2 and α>-IFN, respectively. The effective rate of FFKSIL, IL-2, and α-IFN in a combination was significantly superior to single pharmacotherapy. The effective rate of fufangkushen plus ct-IFN was highest. The effect of FFKSIL, IL-2, and α-IFN, in a combination, on lung cancer with pleural effusions was significantly better than single pharmacotherapy. Moreover, the effect of FFKSIL plus IL-2 or α-IFN had the greatest effect (Hu & Mei, 2012).

Gastric Cancer

Administration of FFKSIL significantly enhanced serum IgA, IgG, IgM, IL-2, IL-4 and IL-10 levels, decreased serum IL-6 and TNF-αlevels, lowered the levels of lipid peroxides and enhanced GSH levels and activities of GSH-dependent enzymes. Our results suggest that FFKSIL blocks experimental gastric carcinogenesis by protecting against carcinogen-induced oxidative damage and improving immunity activity (Zhou et al., 2012).

Colorectal Cancer; Chemotherapy

Eighty patients after colorectal cancer resection were randomly divided into two groups: 40 patients in the control group were treated with routine chemotherapy including 5-fluorouridine(5-FU), calcium folinate(CF) and oxaliplatin, and 40 patients in the experimental group were treated with the same chemotherapy regime combined with 20 mLád-1 compound Kushen injection, for 10d during chemotherapy. In the control group the numbers of CD3+,CD4+T cells,NK cells and CD4+/CD8+ ratio significantly declined relative to prior to chemotherapy (P < 0.05), while CD8+T lymphocyte number increased significantly. In the experimental group, there were no significant differences between the numbers of CD3+,CD4+,CD8+T cells ,NK cells, and CD4+/CD8+ ratio, before and after chemotherapy (P > 0.05).

Compound Kushen injection can improve the immunologic function of patients receiving chemotherapy after colorectal cancer resection (Chen, Yu, Yuan, & Yuan, 2009).

NSCLC; Chemotherapy

A total of 286 patients with advanced NSCLC were enrolled for study. The patients were treated with either compound Kushen injection in combination with NP (NVB + CBP) chemotherapy (vinorelbine and carboplatin, n = 144), or with NP (NVB + CBP) chemotherapy alone (n = 142). The following indicators were observed: levels of Hb, WBC, PLT and T cell subpopulations in blood, serum IgG level, short-term  efficacy, adverse effects and quality of life.

The gastrointestinal reactions and the myelosuppression in the combination chemotherapy group were alleviated when compared with the chemotherapy alone group, showing a significant difference (P < 0.05). CD (8)(+) cells were markedly declined in the combination chemotherapy group, and the CD (4)(+)/CD (8)(+) ratio showed an elevation trend in the chemotherapy alone group. The Karnofsky Performance Scale (KPS) scores and serum IgM and IgG levels were higher in the combination chemotherapy group than those in the chemotherapy alone group (P < 0.01 and P < 0.05).

The compound Kushen injection plus NP chemotherapy regimen showed better therapeutic effect, reduced adverse effects of chemotherapy and improved the quality of life in patients with stage III and IV NSCLC (Fan et al., 2010).

Lung Adenocarcinoma

Different concentrations of matrine injection could inhibit the growth of SPCA/I human lung adenocarcinoma cells. There was a positive correlation between the inhibition rate and the drug concentration. Different concentrations of matrine injection combined with anti-tumor drugs had a higher growth inhibition rate than anti-tumor drugs alone. Matrine injection has direct growth suppression effect on SPCA/I human lung adenocarcinoma cells and SS+ injection combined with anti-tumor drugs shows a significant synergistic effect on tumor cells (Zhu, Jiang, Lu, Guo, & Gan, 2008).

Liver Cancer

Fifty-seven patients with unresectable primary liver cancer were randomly divided into 2 groups. The treatment group with 27 cases was treated by TACE combined with composite Kushen injection, and the control group with 30 cases was treated by TACE alone. One, two, and three year survival rates of the treatment group were 67%, 48%, and 37% respectively, and those of control group were 53%, 37%, and 20% respectively. There were significant differences between both groups (P < 0.05).

Combined TACE with composite Kushen injection can increase the efficacy of patients with unresectable primary liver cancer (Wang & Cheng, 2009).

Chemotherapy

Ten RCTs were included in a meta-analysis, whose results suggest that compared with chemotherapy alone, the combination had a statistically significant benefit in healing efficacy and improving quality of life. As well,  the combination also had a statistically significant benefit in myelosuppression, white blood cell, hematoblast, liver function and in reducing the gastroenteric reaction, decreasing the of CD3, CD4, CD4/CD8, and NK cells (Huang et al., 2011).

Colorectal Cancer, NSCLC, Breast Cancer; Chemotherapy

Fufang kushen Injection might improve the efficacies of chemotherapy in patients with colorectal cancer, NSCLC and breast cancer.

The results of a meta-analysis of 33 studies of randomized controlled trials with a total of 2,897 patients demonstrated that the short-term efficacies in patients with colorectal cancer, NSCLC, and breast cancer receiving Fufangkushen Injection plus chemotherapy were significantly better than for those receiving chemotherapy alone. However the results for patients with gastric cancer on combined chemotherapy were not significantly different from those for patients on chemotherapy alone (Fang, Lin, & Fan, 2011).

References

An, A.J., An, G.W., & Wu, Y.C. (2012). Observation of compound recipe light yellow Sophora root injection combined with chemotherapy in treatment of 35 postoperative patients with breast cancer. Medical & Pharmaceutical Journal of Chinese People”s Liberation Army, 24(10), 43-46. doi: 10.3969/j.issn.2095-140X.2012.10.016.


Chen, G., Yu, B., Yuan, S.J., & Yuan, Q. (2009). Effects of compound Kushen injection on the immunologic function of patients after colorectal cancer resection. Evaluation and Analysis of Drug-Use in Hospitals of China, 2009(9), R735.3. doi: cnki:sun:yypf.0.2009-09-025.


Chen H, Zhang J, Luo J, et al. (2013). Anti-angiogenic effects of oxymatrine on pancreatic cancer by inhibition of the NF-κB-mediated VEGF signaling pathway. Oncol Rep, 30(2):589-95. doi: 10.3892/or.2013.2529.


Fan, C.X., Lin, C.L., Liang, L., Zhao, Y.Y., Liu, J., Cui, J., Yang, Q.M., Wang, Y.L., & Zhang, A.R. (2010). Enhancing effect of compound Kushen injection in combination with chemotherapy for patients with advanced non-small-cell lung cancer. Chinese Journal of Oncology, 32(4), 294-297.


Fang, L., Lin, N.M., Fan, Y. (2011). Short-term  efficacies of Fufangkushen Injection plus chemotherapy in patients with solid tumors: a meta-analysis of randomized trials. Zhonghua Yi Xue Za Zhi, 91(35):2476-81.


Hu, D.J., & Mei, X.D. (2012). Observing therapeutic efficiency of fufangkushen injection, IL-2, α-IFN on lung cancer accompanied with malignancy pleural effusions. Journal of Clinical Pulmonology, 17(10), 1844-1845.


Huang S, Fan W, Liu P, Tian J. (2011). Meta-analysis of compound matrine injection combined with cisplatin chemotherapy for advanced gastric cancer. Zhongguo Zhong Yao Za Zhi, 36(22):3198-202.


Kong, Q-Z., Huang, D-S., Huang, T. et al. (2003). Experimental study on inhibiting angiogenesis in mice S180 by injections of three traditional Chinese herbs. Chinese Journal of Hospital Pharmacy, 2003-11. doi: CNKI:SUN:ZGYZ.0.2003-11-002


Li T, Wong VK, Yi XQ, et al. (2010). Matrine induces cell anergy in human Jurkat T cells through modulation of mitogen-activated protein kinases and nuclear factor of activated T-cells signaling with concomitant up-regulation of anergy-associated genes expression. Biol Pharm Bull, 33(1):40-6.


Ling Q, Xu X, Wei X, et al. (2011). Oxymatrine induces human pancreatic cancer PANC-1 cells apoptosis via regulating expression of Bcl-2 and IAP families, and releasing of cytochrome c. J Exp Clin Cancer Res, 30:66. doi: 10.1186/1756-9966-30-66.


Qi, L., Zhang, J., Zhang, Z. (2013). Determination of four alkaloids in Compound Kushen Injection by high performance liquid chromatography with ionic liquid as mobile phase additive. Chinese Journal of Chromatography, 31(3): 249-253. doi: 10.3724/SP.J.1123.2012.10039.


Shi, B., & Xu, H. (2012). Effects of compound radix Sophorae flavescentis injection on proliferation, apoptosis and caspase-3 expression in adenoid cystic carcinoma ACC-2 cells. Chinese Pharmacological Bulletin, 5(10), 721-724.


Sun M, Cao H, Sun L, et al. (2012). Anti-tumor activities of kushen: literature review. Evid Based Complement Alternat Med, 2012:373219. doi: 10.1155/2012/373219.


Wang, H.M., & Cheng, X.M. (2009). Composite Ku Shen injection combined with hepatic artery embolism on unresectable primary liver cancer. Modern Journal of Integrated Traditional Chinese and Western Medicine, 18(2), 1334–1335.


Xia, G. (2013). Clinical observation of compound matrine injection combined with SP regimen in advanced gastric cancer. Journal of Liaoning Medical University, 2013(1), 37-38.


Yin, W.H., Sheng, J.W., Xia, H.M., Chen, J., Wu, Y.W., & Fan, H.Z. (2013). Study on the effect of compound matrine on the level of sIL-2R and IL-8 in peripheral blood cells of patients with rectal cancer to radiation. Global Traditional Chinese Medicine, 2013(2), 100-104.


Zhang Y, Sun S, Chen J, et al. (2013). Oxymatrine induces mitochondria dependent apoptosis in human osteosarcoma MNNG/HOS cells through inhibition of PI3K/Akt pathway. Tumor Biol.


Zhou, S-K., Zhang, R-L., Xu, Y-F., Bi, T-N. (2012) Anti-oxidant and Immunity Activities of Fufang Kushen Injection Liquid. Molecules 2012, 17(6), 6481-6490; doi:10.3390/molecules17066481


Zhu, M.Y., Jiang, Z.H., Lu, Y.W., Guo, Y., & Gan, J.J. (2008). Matrine and anti-tumor drugs in inhibiting the growth of human lung cancer cell line. Journal of Chinese Integrative Medicine, 6(2), 163-165. doi: 10.3736/jcim20080211.

anti-apoptotic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Autophagy, BAX, Bcl-2, Breast cancer, cancer stem cells, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, CSCs, EpCAM, Esophageal cancer, FAK, G0/G1, G1, G2/M, Glioblastoma, induces apoptosis, Leukemia, Liver cancer, metastasis, Ovarian cancer, p21, p53, Prostate cancer, Prostate cancer cell lines, Rabdosia rubescens, Rectal cancer, TrxR

Oridonin

Cancer: Prostate

Action: Growth arrest, autophagy

To investigate the mechanism of oridonin (ORI)-induced autophagy in prostate cancer PC-3 cells, PC-3 cells cultured in vitro were treated with ORI, and the inhibitory ratio of ORI on PC-3 cells was assayed by 3-4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. After ORI treatment, the proliferation of PC-3 cells was inhibited significantly in a concentration and time-dependent manner. SEM examination revealed cellular shrinkage and disappearance of surface microvilli in ORI-treated cells. Under TEM examination, the nuclei exhibited chromatin condensation and the appearance of a large number of autophagosomes with double-membrane structure in cytoplasm. AO staining showed the existence of AVOs. The expression of LC3 and the mRNA level of beclin 1 was increased by ORI. Furthermore, autophagy inhibitor 3-methyladenine reversed the increase of beclin 1 mRNA. The growth of PC-3 cells was inhibited, and autophagy was induced by ORI, indicating ORI may have a potential antitumor effect.

Source
Ye LH, Li WJ, Jiang XQ, et al. Study on the autophagy of prostate cancer PC-3 cells induced by oridonin. Anat Rec (Hoboken). 2012 Mar;295(3):417-22. doi: 10.1002/ar.21528.

 

Cancer: Multiple myeloma

Action: Inhibits proliferation and induces apoptosis

This study was purposed to investigate the antitumor effect of oridonin on human multiple myeloma cell line U266 The results showed that the oridonin obviously inhibited the growth of U266 cell in dose-and time-dependent manners. As for morphological changes, characteristic apoptotic cells presented in U266 cells treated with 10 µmol/L oridonin for 24 hours. The apoptotic rate of U266 cells increased in dose and time dependent manners; after treatment of U266 cells with oridonin the mRNA levels of FGFR3, BCL2, CCND1 and MYC as well as the their protein levels decreased. Occasionally, the oridonin up-regulated the protein levels of P53 in the same manner. It is concluded that the oridonin can exert its anti-tumor effect by inhibiting proliferation and inducing apoptosis of U266 cell in dose dependent and time dependent manners, that maybe give the clues about new program of target therapy for multiple myeloma.

Source:

Duan HQ, Li MY, Gao L, et al. Mechanism concerning antitumor effect of oridonin on multiple myeloma cell line U266. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Apr;22(2):364-9. doi: 10.7534/j.issn.1009-2137.2014.02.018.

Cancer: Multiple myeloma

Action: Induces apoptosis and autophagy

Exposure to oridonin (1-64 μmol/L) inhibited the proliferation of RPMI8266 cells in a concentration-dependent manner with an IC(50) value of 6.74 μmol/L. Exposure to oridonin (7 μmol/L) simultaneously induced caspase 3-mediated apoptosis and Beclin 1-dependent autophagy of RPMI8266 cells. Both the apoptosis and autophagy were time-dependent, and apoptosis was the main effector pathway of cell death. Exposure to oridonin (7 μmol/L) increased intracellular ROS and reduced SIRT1 nuclear protein in a time-dependent manner.

Oridonin simultaneously induces apoptosis and autophagy of human multiple myeloma RPMI8266 cells via regulation of intracellular ROS generation and SIRT1 nuclear protein. The cytotoxicity of oridonin is mainly mediated through the apoptotic pathway, whereas the autophagy protects the cells from apoptosis.

Source

Zeng R, Chen Y, Zhao S, Cui GH.Autophagy counteracts apoptosis in human multiple myeloma cells exposed to oridonin in vitro via regulating intracellular ROS and SIRT1. Acta Pharmacol Sin. 2012 Jan;33(1):91-100. doi: 10.1038/aps.2011.143.

Cancer: Prostate, acute promyelocytic leukemia, breast, non-small-cell lung (NSCL), Ehrlich ascites, P388 lymphocytic leukemia, colorectal., ovarian, esphageal

Action: Chemoresistance, Ara-C, VP-16 

Cancer cell arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. Weng et al., (2014) compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S–mediated apoptosis.

Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells.

Reference

Weng Hy, Huang Hl, Dong B, et al. Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S. Cancer Res; 74(16); 1–11. doi: 10.1158/0008-5472.CAN-13-1748

Action: Induces apoptosis

Oridonin is a tetracycline diterpenoid isolated from the plant Rabdosia rubescens (RR) [(Hemsl.). Hara (Lamiaceae)] (dong ling cao) is a Chinese medicinal herb used widely in provinces including Henan. The aerial parts of RR and other species of the same genus has been reported to have the functions of clearing “heat” and “toxicity”, nourishing “yin”, removing “blood stasis”, and relieving swelling. RR has been used to treat stomach-ache, sore throat and cough.

Gastric Cancer, Esophageal Cancer, Liver Cancer, Prostate Cancer

RR and its extracts have been shown to be able to suppress disease progress, reduce tumor burden, alleviate syndrome and prolong survival in patients with gastric carcinoma, esophageal., liver and prostate cancers (Tang & Eisenbrand, 1992). Interestingly, other Isodon plants including Isodon japonicus Hara (IJ) and I. trichocarpus (IT) are also applied as home remedies for similar disorders in Japan and Korea.

Induces Apoptosis

These reports suggest that Isodon plants should have at least one essential anti-tumor component. In the 1970s, a bitter tetracycline diterpenoid compound, oridonin, was isolated from RR, IJ, and IT separately, and was shown to be a potent apoptosis inducer in a variety of cancer cells (Fujita et al., 1970; Fujita et al., 1976; Henan Medical Institute, 1978; Fujita et al., 1988).

Anti-cancer

There is currently research being undertaken regarding the relationship between the chemical structure/modifications and the molecular mechanisms underlying its anti-cancer activity, such as suppression of tumor proliferation and induction of tumor cell death, and the cell signal transduction in anti-cancer activity of oridonin (Zhang et al., 2010).

Prostate Cancer, Breast Cancer, NSCLC, Leukemia, Glioblastoma

Oridonin has been found to effectively inhibit the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small-cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138).

Oridonin induced apoptosis and G0/G1 cell-cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in a p53-dependent manner. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell-cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies (Ikezoe et al., 2003).

Breast Cancer; Anti-metastatic

According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell-cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. The induced apoptotic effect of oridonin was further confirmed by a morphologic characteristics assay and TUNEL assay. Meanwhile, oridonin significantly suppressed MDA-MB-231 cell migration and invasion, decreased MMP-2/MMP-9 activation and inhibited the expression of Integrin β1 and FAK. In conclusion, oridonin inhibited growth and induced apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also inhibited tumor invasion and metastasis in vitro possibly via decreasing the expression of MMPs and regulating the Integrin β1/FAK pathway in MDA-MB-231 cells (Wang et al., 2013).

Gastric Cancer

The inhibitory effect of oridonin on gastric cancer HGC-27 cells was detected using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After treated with oridonin (0, 1.25, 2.5, 5 and 10 µg/mL), HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis, and oridonin- induced apoptosis in HGC-27 cells was detected.

Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h (1.25, 2.5, 5 and 10 µg/mL) were 1.78% ± 0.36%, 4.96% ± 1.59%, 10.35% ± 2.76% and 41.6% ± 4.29%, respectively, which showed a significant difference (P < 0.05. Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining. After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. However, the change in the release of LDH caused by necrosis was insignificant, suggesting that the major cause of oridonin-induced HGC-27 cell death was apoptosis. Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls (P < 0.05).

Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway (Sun et al., 2012).

Ehrlich Ascites, Leukemia

Oridonin has been found to also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia. Oridonin triggered apoptosis in more than 50% of t(8;21) leukemic cells in vitro at concentration of 2 M or higher accompanied by degradation of AE oncoprotein, and showed significant anti-leukemia efficacies with low adverse effects in vivo. These data suggest possible beneficial effects for patients with t(8;21) acute myeloid leukemia (AML) (Zhou et al., 2007).

Prostate Cancer, Breast Cancer, Ovarian Cancer

Oridonin exhibited anti-proliferative activity toward all cancer cell lines tested, with an IC50 estimated by the MTT cell viability assay ranging from 5.8+/-2.3 to 11.72+/-4.8 microM. The increased incidence of apoptosis, identified by characteristic changes in cell morphology, was seen in tumor lines treated with oridonin. Notably, at concentrations that induced apoptosis among tumor cells, oridonin failed to induce apoptosis in cultures of normal human fibroblasts. Oridonin up-regulated p53 and Bax and down-regulated Bcl-2 expression in a dose-dependent manner and its absorption spectrum was measured in the presence and absence of double stranded (ds) DNA. Oridonin inhibits cancer cell growth in a cell-cycle specific manner and shifts the balance between pro- and anti-apoptotic proteins in favor of apoptosis. The present data suggest that further studies are warranted to assess the potential of oridonin in cancer prevention and/or treatment (Chen et al., 2005).

Ovarian Cancer Stem Cells; Chemotherapy Resistance

Oridonin was suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these types of compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Colorectal Cancer

Oridonin induced potent growth inhibition, cell-cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice.

Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell-cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment as it has been shown to induce apoptosis and senescence of colon cancer cells in vitro and in vivo (Gao et al., 2010).

Colon Cancer; Apoptosis

Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin.

Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process.

Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate (Gao et al., 2012).

Prostate Cancer; Apoptosis

Oridonin (ORI) could inhibit the proliferation and induce apoptosis in various cancer cell lines. After ORI treatment, the proliferations of human prostate cancer (HPC) cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell-cycle arrest at the G2/M phase. Autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis (Li et al., 2012).

References

Chen S, Gao J, Halicka HD, et al. (2005). The cytostatic and cytotoxic effects of oridonin (Rubescenin), a diterpenoid from Rabdosia rubescens, on tumor cells of different lineage. Int J Oncol, 26(3):579-88.

 

Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.

 

Fujita E, Fujita T, Katayama H, Shibuya M. (1970). Terpenoids. Part XV. Structure and absolute configuration of oridonin isolated from Isodon japonicus trichocarpus. J Chem Soc (Chem Comm), 21:1674–1681

 

Fujita E, Nagao Y, Node M, et al. (1976). Anti-tumor activity of the Isodon diterpenoids: structural requirements for the activity. Experientia, 32:203–206.

 

Fujita T, Takeda Y, Sun HD, et al. (1988). Cytotoxic and anti-tumor activities of Rabdosia diterpenoids. Planta Med, 54:414–417.

 

Henan Medical Institute, Henan Medical College, Yunnan Institute of Botany. (1978). Oridonin–a new anti-tumor subject. Chin Science Bull, 23:53–56.

 

Ikezoe T, Chen SS, Tong XJ, et al. (2003). Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol, 23(4):1187-93.

 

Gao FH, Hu XH, Li W, Liu H, et al. (2010). Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer, 10:610. doi: 10.1186/1471-2407-10-610.

 

Gao FH, Liu F, Wei W, et al. (2012). Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells. Int J Mol Med, 29(4):649-55. doi: 10.3892/ijmm.2012.895.

 

Li X, Li X, Wang J, Ye Z, Li JC. (2012) Oridonin up-regulates expression of P21 and induces autophagy and apoptosis in human prostate cancer cells. Int J Biol Sci. 2012;8(6):901-12. doi: 10.7150/ijbs.4554.

 

Sun KW, Ma YY, Guan TP, et al. (2012). Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway. World J Gastroenterol, 18(48):7166-74. doi: 10.3748/wjg.v18.i48.7166.

 

Tang W, Eisenbrand G. (1992). Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine. Berlin: Springer-Verlag, 817–847.

 

Wang S, Zhong Z, Wan J, et al. (2013). Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. Am J Chin Med, 41(1):177-96. doi: 10.1142/S0192415X13500134.

 

Zhang Wj, Huang Ql, Hua Z-C. (2010). Oridonin: A promising anti-cancer drug from China. Frontiers in Biology, 5(6):540-545.

 

Zhou G-B, Kang H, Wang L, et al. (2007). Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent anti-tumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood, 109(8):3441-3450.

Akt, angiogenesis, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, apoptosis-inducing, Apoptotic, Bcl-xL, Breast cancer, CCNE2, CDK2, CDK4, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, chemo-preventive, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, CSCs, EpCAM, G2/M, hepato-protective, IL-6, Immunomodulatory, including Terminalia chebula, inflammation, inhibits VEGF, iNOS, JNK, Lung cancer, Mcl-1, metastasis, Nitric Oxide, Ovarian cancer, p53, p65, Pancreatic cancer, PGE2, Pro-apoptotic, Radio-protective, TAM chemo-sensitizer, TAM resistance, TNF, TRAIL, VEGF, VEGF

Luteolin

Cancer: Colorectal., pancreatic, ovarian, breast

Action: Anti-inflammatory, radio-protective, TAM chemo-sensitizer

Luteolin is a flavonoid found in many plants and foods, including Terminalia chebula (Retz.), Prunella vulgaris (L.) and Perilla frutescens [(L.) Britton].

Luteolin is contained in Ocimum sanctum L. or Ocimum tenuiflorum L, commonly known as Holy Basil in English or Tulsi in various Indian languages; it is an important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia. Scientific studies have shown it to possess anti-inflammatory, anti-analgesic, anti-pyretic, anti-diabetic, hepato-protective, hypolipidemic, anti-stress, and immunomodulatory activities. It has been found to prevent chemical-induced skin, liver, oral., and lung cancers and mediates these effects by increasing the anti-oxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis.

Radio-protective

The aqueous extract of Tulsi has been shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. The chemo-preventive and radio-protective properties of Tulsi emphasize aspects that warrant future research to establish its activity and utility in cancer prevention and treatment (Baliga et al., 2013).

Anti-inflammatory

Pre-treatment of RAW 264.7 with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-αand interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-αrelease. From the compounds tested luteolin and quercetin were the most potent in inhibiting cytokine production with an IC50 of less than 1 and 5 µM for TNF-αrelease, respectively. Pre-treatment of the cells with luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IκB-αphosphorylation and reduced the levels of IκB-α. It was concluded that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-κB-mediated gene expression and pro-inflammatory cytokine production in murine macrophages (Xagorari et al., 2001).

Luteolin (Lut) possesses significant anti-inflammatory activity in well established models of acute and chronic inflammation, such as xylene-induced ear edema in mice (ED50= 107 mg/ kg), carrageenin-induced swellingof the ankle, acetic acid-induced pleurisy and croton oil-induced gaseous pouch granuloma in rats. Its combined immunostimulatory and anti-inflammatory activity, and inhibitory effect upon immediate hypersensitive response provide the pharmacologic bases for the beneficial effects of Lut in the treatment of chronic bronchitis (Chen et al., 1986).

Anti-inflammatory; Lung

Luteolin dose-dependently inhibited the expression and production of nitric oxide (NO) and prostaglandin E2 (PGE2), as well as the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Luteolin also reduced the DNA binding activity of nuclear factor-kappa B (NF-κB) in LPS-activated macrophages. Moreover, luteolin blocked the degradation of IκB-α and nuclear translocation of NF-κB p65 subunit.

In sum, these data suggest that, by blocking NF-κ>B and AP-1 activation, luteolin acts to suppress the LPS-elicited inflammatory events in mouse alveolar macrophages, and this effect was mediated, at least in part, by inhibiting the generation of reactive oxygen species. These observations suggest a possible therapeutic application of this agent for treating inflammatory disorders in the lung (Chen et al., 2007).

Anti-inflammatory; Neuroinflammation

Pre-treatment of primary murine microglia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 hours after injection. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation (Jang et al., 2008).

Colon Cancer

Activities of CDK4 and CDK2 decreased within 2 hours after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 µmol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2.

tLuteolin promoted G2/M arrest at 24 hours post-treatment  by down-regulating cyclin B1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21CIP1/WAF1, survivin, Mcl-1, Bcl-xL, and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. Lim et al., (2007) demonstrated that luteolin promotes both cell-cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its anti-tumorigenic activities.

Pancreatic Cancer; Chemotherapy

Simultaneous treatment or pre-treatment (0, 6, 24 and 42 hours) of flavonoids and chemotherapeutic drugs and various concentrations (0-50µM) were assessed using the MTS cell proliferation assay. Simultaneous treatment with either flavonoid (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60h resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of either Api or Lut, followed by Gem for 36 hours was optimal to inhibit cell proliferation.

Pre-treatment of cells with 11-19µM of either flavonoid for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Lut (15µM, 24h) Pre-treatment followed by Gem (10µM, 36h), significantly decreased protein expression of nuclear GSK-3βand NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of Lut effectively aid in the anti-proliferative activity of chemotherapeutic drugs (Johnson et al., 2013).

Ovarian Cancer

Luteolin has been found to repress NF-kappaB (NF-κ>B, a pro-inflammatory transcription factor) and inhibit pro-inflammatory cytokines such as TNF-αand IL-6. Additionally, it has been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance.

Recent studies further indicate that luteolin potently inhibits VEGF production and suppresses ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Chemo-sensitizer

The sensitization effect of luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to luteolin and cisplatin. Second, Shi et al., (2007) observed a significant increase of p53 protein level in luteolin-treated cancer cells without increase of p53 mRNA level, indicating the possible effect of luteolin on p53 posttranscriptional regulation.

In summary, data from this study reveal a novel molecular mechanism involved in the anti-cancer effect of luteolin and support its potential clinical application as a chemo-sensitizer in cancer therapy.

Breast Cancer; TAM Chemo-sensitizer

This study found that the level of cyclin E2 (CCNE2) mRNA was higher in tumor cells (4.89-fold, (∗)P=0.005) than in normal paired tissue samples as assessed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (n=257). Further, relatively high levels of CCNE2 protein expression were detected in tamoxifen-resistant (TAM-R) MCF-7 cells.

These results showed that the level of CCNE2 protein expression was specifically inhibited in luteolin-treated (5µM) TAM-R cells, either in the presence or absence of 4-OH-TAM (100nM). Combined treatment with 4-OH-TAM and luteolin synergistically sensitized the TAM-R cells to 4-OH-TAM. The results of this study suggest that luteolin can be used as a chemo-sensitizer to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients (Tu et al., 2013).

References

Baliga MS, Jimmy R, Thilakchand KR, et al. (2013). Ocimum sanctum L (Holy Basil or Tulsi) and its phytochemicals in the prevention and treatment of cancer. Nutr Cancer, 65(1):26-35. doi: 10.1080/01635581.2013.785010.


Chen CY, Peng WH, Tsai KD and Hsu SL. (2007). Luteolin suppresses inflammation-associated gene expression by blocking NF-κB and AP-1 activation pathway in mouse alveolar macrophages. Life Sciences, 81(23-24):1602-1614. doi:10.1016/j.lfs.2007.09.028


Chen MZ, Jin WZ, Dai LM, Xu SY. (1986). Effect of luteolin on inflammation and immune function. Chinese Journal of Pharmacology and Toxicology, 1986-01.


Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.


Jang S, Kelley KW, Johnson RW. (2008). Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. PNAS, 105(21):7534-7539


Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, S0278-6915(13)00491-2. doi: 10.1016/j.fct.2013.07.036.


Lim DY, Jeong Y, Tyner Al., Park JHY. (2007). Induction of cell-cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol, 292: G66-G75. doi:10.1152/ajpgi.00248.2006.


Shi R, Huang Q, Zhu X, et al. (2007). Luteolin sensitizes the anti-cancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Molecular Cancer Therapeutics, 6(4):1338-1347. doi: 10.1158/1535-7163.MCT-06-0638.


Tu SH, Ho CT, Liu MF, et al. (2013). Luteolin sensitizes drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem, 141(2):1553-61. doi: 10.1016/j.foodchem.2013.04.077.


Xagorari A, Papapetropoulos A, Mauromatis A, et al. (2001). Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and pro-inflammatory cytokine production in macrophages. JPET, 296(1):181-187.

Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, Apoptotic, BAX, Bcl-2, Chapter 8 Injectables and Cancer Research, Chemo-protective, Chemotherapy, Colon Cancer or Colorectal cancer, CSK, Doxorubicin-induced cardotoxicity, Hippophae rhamnoides, Lung cancer, Lymphoma, radiotherapy, Rectal cancer

Isorhamnetin

Cancer:
Lung, colon, acute myeloid leukemia, T lymphoma, Ehrlich carcinoma, gastric, esophageal squamous cell, chronic myelogenous leukemia

Action: Dox-induced cardiotoxicity, anti-oxidant

Isorhamnetin, the anti-tumor component of Hippophae rhamnoides Linn, is also a member of the ßavonoid class of compounds. Its chemical name is 3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl) chromen-4-one and its molecular formula is C16H12O7.

Lung Cancer

Isorhamnetin shows good inhibitory effects on human lung adenocarcinoma A549 cells, human colon cancer HT-29 cells, human chronic myeloid leukemia K562 cells, human acute myeloid leukemia HL-60 cells, mouse T lymphoma YAC-1 cells and mouse Ehrlich carcinoma. In terms of its mechanism of action, it seems that isorhamnetin simultaneously reduces the expression of Bcl-2 and increases the expression of Bax, which activates caspase-9 and its downstream factor caspase-3, thus resulting in cell death (Zhu et al. 2005).

Colorectal Cancer

It was demonstrated that isorhamnetin prevents colorectal tumorigenesis. Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. Magnetic resonance imaging, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than control diet.

These observations suggest the chemo-protective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression (Saud et al., 2013).

Gastric Cancer

The potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, were investigated on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, gastric cancer (GC) cell lines, and xenograft mice model.

It was observed that IH exerted a strong anti-proliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of gastric cancer cells, which could be reversed in the presence of PPAR-γ inhibitor.

Using molecular docking analysis, Ramachandran et al. (2013) demonstratd that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, these findings clearly indicate that anti-tumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.

Cardiac-protective; Doxorubicin

Isorhamnetin is a natural anti-oxidant with obvious cardiac-protective effect. Its action against doxorubicin-induced cardotoxicity and underlying mechanisms were investigated. Doxorubicin (Dox) is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. The aim of this study is to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p.) administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity.

Daily pre-treatment with isorhamnetin (5 mg/kg, i.p.) for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes, and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox (Sun et al., 2013).

Chronic Myelogenous Leukemia

The isorhamnetin 3-o-robinobioside and its original extract, ethyl acetate extract, from Nitraria retusa leaves, were evaluated for their ability to induce anti-oxidant and anti-genotoxic effects in human chronic myelogenous leukemia cell line. They were shown to have a great anti-oxidant and anti-genotoxic potential on human chronic myelogenous leukemia cell line K562 (Boubaker et al., 2012).

Esophageal Cancer

The flavonol aglycone isorhamnetin shows anti-proliferative activity in a variety of cancer cells and it inhibits the proliferation of human esophageal squamous carcinoma Eca-109 cells in vitro (Shi et al., 2012).

References

Boubaker J, Ben Sghaier M, Skandrani I, et al. (2012). Isorhamnetin 3-O-robinobioside from Nitraria retusa leaves enhance anti-oxidant and anti-genotoxic activity in human chronic myelogenous leukemia cell line K562. BMC Complement Altern Med, 12:135. doi: 10.1186/1472-6882-12-135.


Ramachandran L, Manu KA, Shanmugam MK, et al. (2013). Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer. J Biol Chem, 288(26):18777. doi: 10.1074/jbc.A112.388702.


Saud SM, Young MR, Jones-Hall YL, et al. (2013). Chemo-preventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β -catenin. Cancer Res, 73:5473.


Shi C, Fan LY, Cai Z, Liu YY, Yang CL. (2012). Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin. Neoplasma, 59(4):361-9. doi: 10.4149/neo_2012_047.


Sun J, Sun G, Meng X, et al. (2013). Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. PLoS One, 8(5):e64526. doi: 10.1371/journal.pone.0064526.


Zhu L, Wang ZR, Zhou LM, et al. (2005). Effects and mechanisms of isorhamnetin on lung carcinoma. Space Med Med Eng (Chin), 18:381-383.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-tumoral, Anti-tumoral., AP-1, Apoptotic, Breast cancer, c-Jun, Chapter 8 Injectables and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, ERK1, inflammation, Melanoma, p38, PKC, Prostate cancer, Skin cancer

Carnosol

Cancer: Breast, prostate, skin, colon, leukemia, stomach

Action: Anti-inflammatrory, anti-angiogenic

Carnosol is found in certain Mediterranean meats, fruits, vegetables, and olive oil. In particular, it is sourced from rosemary (Rosmarinus officinalis (L.)) and desert sage (Salvia pachyphylla (Epling ex Munz)).

Prostate Cancer, Breast Cancer, Skin Cancer, Colon Cancer, Leukemia

One agent, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals.

This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent (Johnson, 2011).

Literature evidence from animal and cell culture studies demonstrates the anti-cancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells (Ngo et al., 2011).

Anti-inflammatory

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anti-cancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity.

Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms (Subbaramaiah, 2002).

Breast Cancer

Two rosemary components, carnosol and ursolic acid, appear to be partly responsible for the anti-tumorigenic activity of rosemary. Supplementation of diets for 2 weeks with rosemary extract (0.5% by wt) but not carnosol (1.0%) or ursolic acid (0.5%) resulted in a significant decrease in the in vivo formation of rat mammary DMBA-DNA adducts, compared to controls. When injected intraperitoneally (i.p.) for 5 days at 200 mg/kg body wt, rosemary and carnosol, but not ursolic acid, significantly inhibited mammary adduct formation by 44% and 40%, respectively, compared to controls. Injection of this dose of rosemary and carnosol was associated with a significant 74% and 65% decrease, respectively, in the number of DMBA-induced mammary adenocarcinomas per rat, compared to controls. Ursolic acid injection had no effect on mammary tumorigenesis.

Therefore, carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent (Singletary et al., 1996).

Anti-angiogenic

The anti-angiogenic activity of carnosol and carnosic acid could contribute to the chemo-preventive, anti-tumoral and anti-metastatic activities of rosemary extracts and suggests that there is potential in the treatment of other angiogenesis-related malignancies (L-pez-JimŽnez et al., 2013).

References:

Johnson JJ. (2011). Carnosol: A promising anti-cancer and anti-inflammatory agent. Cancer Letters, 305(1):1-7. doi:10.1016/j.canlet.2011.02.005.


L-pez-JimŽnez A, Garc'a-Caballero M, Medina Mç, Quesada AR. (2013). Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary. Eur J Nutr, 52(1):85-95. doi: 10.1007/s00394-011-0289-x.


Ngo SN, Williams DB, Head RJ. (2011). Rosemary and cancer prevention: preclinical perspectives. Crit Rev Food Sci Nutr, 51(10):946-54. doi: 10.1080/10408398.2010.490883.


Singletary K, MacDonald C & Wallig M. (1996). Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Letters, 104(1):43-8. doi: 10.1016/0304-3835(96)04227-9


Subbaramaiah K, Cole PA, Dannenberg AJ. (2002). Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms. Cancer Res, 62:2522

Anti-cancer, apoptosis, Apoptotic, Breast cancer, Breast cancer cell lines, Chapter 8 Injectables and Cancer Research, Colon Cancer or Colorectal cancer, Cytostatic, p53

Camptothecin (CPT) & 10-hydroxycamptothecin (HCPT)

Cancer: Breast, colon

Action: Cytostatic

Breast Cancer

Recently, natural product DNA topoisomerase I inhibitors 10-hydroxycamptothecin (HCPT) and camptothecin (CPT) have been shown to have therapeutic effects in both in vitro and in vivo models of human breast cancer. After evaluation, the apoptotic pathways were characterized in vitro and in vivo in the human breast cancer cell lines MCF-7 and MDA-MB-468.

The elevation of p53 protein levels in MCF-7 cells treated with CPT was significantly inhibited by preincubation with DNA breaks inhibitor aphidicolin, while the elevation of p21WAF1/CIP1 protein levels was not inhibited. The elevation of p21WAF1/CIP1 in MDA-MB-468 cells treated with CPT was not inhibited by aphidicolin.

Results suggest that treatment with HCPT and CPT results in increased levels of p21WAF1/CIP1 protein and mRNA, and that they induce apoptosis in human breast cancer cells through both p53-dependent and -independent pathways. Findings may be significant in further understanding the mechanisms of actions of camptothecins in the treatment of human cancers (Liu & Zhang, 1998).

Colon Cancer

10-HCPT significantly repressed the proliferation of Colo 205 cells at a relatively low concentration (5-20 nM). Flow cytometry analysis and western blot and apoptosis assays demonstrated that low-dose 10-HCPT arrested Colo 205 cells in the G2 phase of the cell-cycle and triggered apoptosis through a caspase-3-dependent pathway.

Moreover, following oral administration at doses of 2.5-7.5 mg/kg/2 days, significant suppression of tumor growth by 10-HCPT was observed in mouse xenografts. No acute toxicity was observed after an oral challenge of 10-HCPT in BALB/c-nude mice every 2 days.

Results suggest that a relatively low dose of 10-HCPT (p.o.) is able to inhibit the growth of colon cancer, facilitating the development of a new protocol of human trials with this anti-cancer drug (Ping et al., 2006).

References

Liu, W., & Zhang, R. (1998). Up-regulation of p21WAF1/CIP1 in human breast cancer cell lines MCF-7 and MDA-MB-468 undergoing apoptosis induced by natural product anti-cancer drugs 10-hydroxycamptothecin and camptothecin through p53-dependent and independent pathways. International Journal of Oncology, 12(4), 793-804.


Ping, Y.H., Lee, H.C., Lee, J.Y., et al. (2006). Anti-cancer effects of low-dose 10-hydroxycamptothecin in human colon cancer. Oncology Reports, 15(5), 1273-9.

Anti-cancer, apoptosis, Bcl-2, Breast cancer, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, G0/G1, G1, GM-CSF, IL-2, IL-6, IL-8, Lung cancer, TNF

Astragalus (huang qi)

Cancer: Non-small-cell lung cancer, breast, colon, stomach

NSCLC; Chemotherapy

Guo et al. (2012) reported that treatment with Astragalus polysaccharide (APS) injections integrated with vinorelbine and cisplatin significantly improved quality of life in patients with advanced non-small-cell lung cancer over vinorelbine and cisplatin alone.

NSCLC

Astragalus injection (AI) combined with chemotherapy can significantly improve the QOF in NSCLC patients of advanced stage. The effective rate in the treated group was 40.0% and in the control group was 36.7%, the mean remission rate in the treated and control group was 5.4 months and 3.3 months, the median survival period 11 months and 7 months, and the 1-year survival rate 46.75% and 30.0%, respectively; the differences of these indexes between the two groups were all significant (P < 0.05). Moreover, the clinical improving rate and QOF elevation rate in the treated group was 80.4% and 43.3%, as compared with those in the control group (50.0% and 23.3% respectively); the difference was also significant (P < 0.01) (Zou & Liu, 2003).

Breast Cancer

In physiological dose E2, Astragalus mongholicus injection inhibited MCF-7 breast cancer cells proliferation at all concentration groups. As time lasting, Astragalus mongholicus injection showed better inhibitory effect than TAM (P<0.05). Among 2 x 10(-1) g/mL-2 x 10(-4) g/mL concentration, Astragalus mongholicus injection significantly increased the proliferative percent of G0/G1 and S-phase cell, decreased percent of G2-M phase cell (P<0.05) at 24 hours. After cocultured 72 hours, Astragalus mongholicus injection increased the rate of apoptosis to 16.7% at 2 x 10(-1) g/mL concentration (Zhou, Liu, & Tan, 2009).

Acute Exacerbations, Respiratory Failure in Chronic Obstructive Pulmonary Disease

A total of 112 patients with acute chronic obstructive pulmonary disease (AECOPD)were randomly divided into the treatment group (56 cases) and control group (56 cases). The treatment group received a 40 mL astragalus injection, with 5% glucose, 250 mL intravenous drip once a day at the start of conventional therapy. The control group received conventional therapy only. The therapeutic course of both groups was 14 days, and clinical therapeutic effects were observed. Serum levels of TNF-α>, IL-8, IL-2, lung function and blood gas analysis index of both groups were measured before and after treatment. The treatment group”s effectiveness rate was 94.64%, compared to the control group”s 67.86%, which was statistically significant (P<0.05).

Astragalus injection may significantly decrease the serum levels of TNF-α and IL-8, and increase the level of IL-2. It may improve the lung function and the curative effect in the patients with AECOPD (Xiong, Guo, & Xiong, 2013).

Residual Renal Function

The effect of astragalus injection on hemodialysis patient”s RRF (residual renal function, RRF) was observed.

Sixty hemodialysis patients with a RRF of more than 2ml/min were randomly divided into either an astragalus injection treatment group or a control group treated with normal saline. One hour prior to hemodialysis completion, the treatment group was administered an astragalus injection of 30ml, while the control group was given 30 ml of normal saline. Follow up after 6 months compared data of daily urine output and RRF.

Astragalus injection can potentially delay the rate of daily urine output reduction and protect RRF to some extent (Qi et al., 2013).

Stomach Cancer, Colon Cancer; Oxaliplatin-induced Neurotoxicity

40 patients with stomach or colon cancer were enrolled in the study. Patients comprised of 23 men and 17 women, from the ages of 32-75 years (mean age 60 years), and were randomly divided into two groups: the test group and the control group (20 cases in each group). All patients were treated with one cycle of an Oxaliplatin-containing chemotherapy regimen, entailing: oxaliplatin 130 mg/m2 on day 1, fluorouracil 0.5 g on days 1-5, and calcium foliate 0.2 g on days 1-5. In the test group 30 ml of Huangqi injection was added to the regimen on days 1-7. The manifestation of peripheral neurotoxic reactions were observed and nerve growth factor levels were measured.

In the control group, 2 patients had grade 0 toxicity, 10 had grade 1 toxicity, 6 had grade 2 toxicity, and 2 had grade 3 toxicity. In the test group, 14 patients had grade 0 toxicity and 6 had grade 1 toxicity. The incidence rate of neurotoxicity in the test and control groups was 30% and 90%, respectively. In the test and control groups, the nerve growth factor levels were (167 ± 10) ng/ml and (204 ± 19) ng/ml before chemotherapy, as well as (152 ± 8) ng/ml and (133 ± 12) ng/ml 2 days after chemotherapy, respectively. In the control group, the nerve growth factor levels were markedly decreased 2 days after chemotherapy compared to before chemotherapy. The difference between the two groups was statistically significant (P < 0.01).

Huangqi injection has some degree of efficacy in the prevention and treatment of Oxaliplatin-induced neurotoxicity (Cui, Li, Tan, & Li, 2009).

Myelosuppression

Astragalus membranaceus injection (AMI), administered at (500 mg/kg) improved the hematopoietic microenvironment by enhancing the BMSC survival and proliferation of colony-forming unit-fibroblast (CFU-F) formation, production of IL-6 as well as Granulocyte-macrophage colony-stimulating factor (GM-CSF) by BMSC and bcl-2 protein and mRNA expression in BMSC, which promoted myelopoiesis. The data may provide a mechanistic basis for applying this ancient Chinese herb to promote hematopoiesis as an efficacious adjuvant therapy against myelosuppression induced by anti-cancer therapy (Zhu & Zhu, 2007).

References

Cui, H.J., Li, O.J., Ying, H.Y., & Li, Y. (2009). Clinical observation of efficacy of huangqi injection in the prevention and treatment of neurotoxicity induced by oxaliplatin-containing chemotherapy regimen. Adverse Drug Reactions Journal., 11(4), 1671-8585.


Guo, L., Bai, S.P., Zhao, L., Wang, X.H. (2012). Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small-cell lung cancer: effects on quality of life and survival. Med Oncol. http://dx.doi.org/10.1007/s12032-011-0068-9.


Qi, Y.H., Qu, X.L., Tang, Y.H., Dai, Q., Zhang, S.B., & Yao, C.Y. (2013). The impact of Astragalus injection on residual renal function in hemodialysis patients. New Medicine, 2013(2), 105-107.


Xiong, S., Guo, Y., & Xiong, X. (2013). Influence of astragalus injection on serum cytokines and lung function in acute exacerbation of chronic obstructive pulmonary disease. China Modern Doctor, 51(9), 43-45.


Zhou, R.F., Liu, P.X., Tan, M. (2009). Effect of Astragalus mongholicus injection on proliferation and apoptosis of hormone sensitive (MCF-7) breast cancer cell lines with physiological dose E2. Zhong Yao Cai, 32(5):744-7.


Zou, Y.H., Liu, X.M. (2003). Effect of astragalus injection combined with chemotherapy on quality of life in patients with advanced non-small-cell lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi, 23(10):733–735.


Zhu XL, Zhu BD. (2007). Mechanisms by which Astragalus membranaceus injection regulates hematopoiesis in myelosuppressed mice. Phytother Res, 21(7):663-7.

ABCG2, AIF, anti-apoptotic, Anti-cancer, Anti-metastatic, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Artemisia annua, Bcl-2, BCRP, Breast cancer, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, Derivative of artemisinin, Down-regulates, epidermal growth factor receptor, Esophageal cancer, G0/G1, G1, G2/M, ICAM-1, induces apoptosis, Lymphoma, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, Osteosarcoma, Ovarian cancer, p21, p53, Pancreatic cancer, Prostate cancer, Radio-sensitizer, Sarcoma, Skin cancer

Artesunate

Cancer: Colon, esophageal., pancreatic, ovarian, multiple myeloma and diffuse large B-cell lymphoma, osteosarcoma, lung, breast, skin, leukemia/lymphoma

Action: Anti-metastatic, MDR, radio-sensitizer

Pulmonary Adenocarcinomas

Artesunate exerts anti-proliferative effects in pulmonary adenocarcinomas. It mediates these anti-neoplastic effects by virtue of activating Bak (Zhou et al., 2012). At the same time, it down-regulates epidermal growth factor receptor expression. This results in augmented non-caspase dependent apoptosis in the adenocarcinoma cells. Artesunate mediated apoptosis is time as well as dose-dependent. Interestingly, AIF and Bim play significant roles in this Bak-dependent accentuated apoptosis (Ma et al., 2011). Adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) expression is also attenuated while transcription of matrix metallopeptidase 7 (MMP-7) is also down-regulated (Zhao et al., 2011). In addition, arsenuate enhances the radio-sensitization of lung carcinoma cells. It mediates this effect by down-regulating cyclin B1 expression, resulting in augmented G2/M phase arrest (Rasheed et al., 2010).

Breast Cancer

Similarly, artesunate exhibits anti-neoplastic effects in breast carcinomas. Artesunate administration is typically accompanied by attenuated turnover as well as accentuated peri-nuclear localization of autophagosomes in the breast carcinoma cells. Mitochondrial outer membrane permeability is typically augmented. As a result, artesunate augments programmed cellular decline in breast carcinoma cells (Hamacher-Brady et al., 2011).

Skin Cancer

Artesunate also exerts anti-neoplastic effects in skin malignancies. It mediates these effects by up-regulating p21. At the same time it down-regulates cyclin D1 (Jiang et al., 2012).

Colon Cancer

Artemisunate significantly inhibited both the invasiveness and anchorage independence of colon cancer SW620 cells in a dose-dependent manner. The protein level of intercellular adhesion molecule 1 (ICAM-1) was down-regulated as relative to the control group.

Artemisunate could potentially inhibit invasion of the colon carcinoma cell line SW620 by down-regulating ICAM-1 expression (Fan, Zhang, Yao & Li, 2008).

Multi-drug resistance; Colon Cancer

A profound cytotoxic action of the antimalarial., artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times (P = 0.00132) and the portion of cells in the G0/G1 (P = 0.02244) or S cell-cycle phases (P = 0.03567).

Efferth et al., (2003) selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data-base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (=12%) genes correlated significantly to the IC50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P = 0.00017).

Multi-drug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent and- independent pathways in isogenic p53+/+ p21WAF1/CIP1+/+, p53-/- p21WAF1/CIP1+/+, and p53+/+ p21WAF1/CIP1-/- colon carcinoma cells.

Multi-drug resistance; Esophageal Cancer

The present study aimed to investigate the correlation between ABCG2 expression and the MDR of esophageal cancer and to estimate the therapeutic benefit of down-regulating ABCG2 expression and reversing chemoresistance in esophageal cells using artesunate (ART).

ART is a noteworthy antimalarial agent, particularly in severe and drug-resistant cancer cases, as ART is able to reverse drug resistance. ART exerted profound anti-cancer activity. The mechanism for the reversal of multi-drug resistance by ART in esophageal carcinoma was analyzed using cellular experiments, but still remains largely unknown (Liu, Zuo, & Guo, 2013).

Pancreatic Cancer

The combination of triptolide and artesunate could inhibit pancreatic cancer cell line growth, and induce apoptosis, accompanied by expression of HSP 20 and HSP 27, indicating important roles in the synergic effects. Moreover, tumor growth was decreased with triptolide and artesunate synergy. Results indicated that triptolide and artesunate in combination at low concentrations can exert synergistic anti-tumor effects in pancreatic cancer cells with potential clinical applications (Liu & Cui, 2013).

Ovarian Cancer

Advanced-stage ovarian cancer (OVCA) has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.

Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations.

However, Marchion et al. (2013) identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral., and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.

Multiple Myeloma, B-cell Lymphoma

Findings indicate that artesunate is a potential drug for treatment of multiple myeloma and diffuse large B-cell lymphoma (DLBCL) at doses of the same order as currently in use for treatment of malaria without serious adverse effects. Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with down-regulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 µm. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 µm. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment (Holien et al., 2013).

Osteosarcoma, Leukemia/Lymphoma

Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo (Xu et al. 2011). ART alone or combined with chemotherapy drugs could inhibit the proliferation of B/T lymphocytic tumor cell lines as well ALL primary cells in vitro, probably through the mechanism of apoptosis, which suggest that ART is likely to be a potential drug in the treatment of leukemia/lymphoma (Zeng et al., 2009).

References

Efferth, T., Sauerbrey, A., Olbrich, A., et al. (2003) Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol, 64(2):382-94.


Fan, Y., Zhang, Y.L., Yao, G.T., & Li, Y.K. (2008). Inhibition of Artemisunate on the invasion of human colon cancer line SW620. Lishizzhen Medicine and Materia Medica Research, 19(7), 1740-1741.


Hamacher-Brady, A., Stein, H.A., Turschner, S., et al. (2011). Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. 2011;286(8):6587–6601. doi: 10.1074/jbc.M110.210047.


Holien, T., Olsen, O.E., Misund, K., et al. (2013). Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol, 91(4):339-46. doi: 10.1111/ejh.12176.


Jiang, Z., Chai, J., Chuang, H.H., et al. (2012). Artesunate induces G0/G1 cell-cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells. Anti-cancer Drugs, 23(6):606–613. doi: 10.1097/CAD.0b013e328350e8ac.


Liu, L., Zuo, L.F., Guo, J.W. (2013). Reversal of Multi-drug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett, 6(5):1475-1481.


Liu, Y. & Cui, Y.F. (2013). Synergism of cytotoxicity effects of triptolide and artesunate combination treatment in pancreatic cancer cell lines. Asian Pac J Cancer Prev, 14(9):5243-8.


Ma, H., Yaom Q., Zhang, A.M., et al. (2011). The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules, 16(12):10556–10569. doi: 10.3390/molecules161210556.


Marchion, D.C., Xiong, Y., Chon, H.S., et al. (2013). Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer. Am J Obstet Gynecol, S0002-9378(13)00827-2. doi: 10.1016/j.ajog.2013.08.004.


Rasheed, S.A., Efferth, T., Asangani, I.A., Allgayer, H. (2010). First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer, 127(6):1475–1485. doi: 10.1002/ijc.25315.


Xu, Q., Li, Z.X., Peng, H.Q., et al. (2011). Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 12(4):247–255. doi: 10.1631/jzus.B1000373.


Zhao, Y., Jiang, W., Li, B., et al. (2011). Artesunate enhances radiosensitivity of human non-small-cell lung cancer A549 cells via increasing no production to induce cell-cycle arrest at G2/M phase. Int Immunopharmacol, 11(12):2039–2046. doi: 10.1016/j.intimp.2011.08.017.


Zeng, Y., Ni, X., Meng, W.T., Wen, Q., Jia, Y.Q. (2009). Inhibitive effect of artesunate on human lymphoblastic leukemia/lymphoma cells. Sichuan Da Xue Xue Bao Yi Xue Ban, 40(6):1038-43.


Zhou, C., Pan, W., Wang, X.P., Chen, T.S. (2012). Artesunate induces apoptosis via a bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol, 227(12):3778–3786. doi: 10.1002/jcp.24086.

Breast cancer, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, Cytostatic, G2/M, Immune, Liver cancer, Lung cancer, Lymphoma, Radio-sensitizer, radiotherapy, Rectal cancer

Ai Di Injection (ADI)

Cancers: Breast, colorectal., glioma, lung

Action: Chemo-sensitizer, cytostatic, radio-sensitizer

 

Ingredients: Mylabris phalerata (ban mao), Panax ginseng (ren shen), Astragalus membranaceus (huang qi).

TCM functions: Clearing Heat, removing Toxin, resolving stagnant Blood, dissolving lumps.

Indications: Primary liver cancer, lung cancer, colorectal cancer, malignant lymphoma, and gynecological malignancies.

Dosage and usage:

For adults: 50-100ml, mixed with 400-500ml of 0.9% NaCl injection or 5-10% glucose injection for intravenous drip, once daily.

When combined with radiotherapy or chemotherapy, the course of treatment is synchronized to radiotherapy or chemotherapy.

Application before or after the surgery: 10 days as a course of treatment.

Intervention treatment: 10 days as a course of treatment.

Single application: 15 days as a cycle, with 3 days interval., 2 cycles as a course of treatment.

 

Cachexia patients in advanced stage: 30 consecutive days as a course of treatment (Drug Information Reference in Chinese: See end).

 

Glioma; Radio-sensitization

The inhibition ratio was determined by MTT assay, the change in the cell-cycle was analyzed by flow cytometry and the expression of cyclin B1 and Wee1 was detected by Western blot analysis. The reproductive activity of the group treated with irradiation (IR) and Aidi injection was suppressed significantly, and the cloning efficiency and divisional index also declined. Aidi injection (15 µg/ml) induced G2/M phase arrest in the cell line after 48 h.

 

Aidi injection (ADI) is effective in radio-sensitization. The possible mechanisms involved may be associated with G2/M phase cell arrest, the down-regulation of cyclin B1 and up-regulation of Wee1 expression, which influences cell size by inhibiting the entry into mitosis, through inhibiting Cyclin-dependent kinase 1 (Xu, Song, Qin, Wang, & Zhou, 2012).

 

Breast Cancer

ADI significantly inhibited the proliferation of MCF-7 cells in a dose-dependent manner. The IC50 of ADI was 55.71 mg/mL after treatment for 48 h. The 60 mg/mL ADI was used as the therapeutic drug concentration. Microarray analysis identified 45 miRNAs that were up-regulated and 55 miRNAs that were down-regulated in response to ADI treatment. Many ADI-induced miRNAs were related to breast cancers. The 12 potential target genes of mir-126 were predicted by both TargetScan and PicTar software.

 

The miRNA may serve as therapeutic targets for ADI, and its modulation of expression is an important mechanism of ADI inhibition of breast cancer cell growth (Zhang, Zhou, Lu, Du, & Su, 2011).

 

Colorectal Cancer; FOLFOX4

A consecutive cohort of 100 patients was divided into two groups. The experimental group was treated with a combination of Aidi injection and FOLFOX4, while the control group was only administered FOLFOX4. After a minimum of two courses of treatment, efficacy, quality of life, and side-effects were evaluated.

 

The response rate of the experimental group was not significantly different compared to the control group (P > 0.05). However, there were significant differences in clinical benefit response and KPS score. In addition, adverse gastrointestinal reactions and the incidence of leukopenia were lower than that of the control group (P < 0.05).

Aidi injection, combined with FOLFOX4, is associated with reduced toxicity of chemotherapy, enhanced clinical benefit response, and improved quality of life in patients with advanced colorectal cancer (Xu, Huang, Li, Li, & Tang, 2011).

 

NSCLC

Ninety-eight cases of advanced NSCLC were randomly divided into two groups: a trial group and control group. In the trial group Navelbine/Cisplatin (NP) plus Ai Di Injection (ADI) (60-80 ml) was administered intravenously, via dissolution in 400 ml of normal saline, per day for 8-10 days. In the control group, only NP chemotherapy was administered at the dosages of: Navelbine (25 mg/m², d1, 8) and Cisplastin (40 mg/m², d1-3). Each patient received at least two cycles of treatment.

 

The effective rate in the trial group and the control group was 53.1% and 44.9% respectively, without significant difference between the two groups (P > 0.05). However, the rate of progression, adverse reactions in the bone marrow, digestive tract, and immune function in the trial group were all lower than those in the control group (P < 0.05). In addition, improvement in Karnofsky score in the trial group was higher than that in the control group (P < 0.05).

 

A chemotherapy regiment of NP, combined with ADI, shows benefit in the treatment of advanced NSCLC. AI could minimize the adverse reactions of chemotherapy, and improve the quality of life in patients with NSCLC (Wang et al., 2004).

 

NSCLC; Meta-analysis

PubMed (1980-2008), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), EMBASE (1984-2008), CancerLit (1996-2003), CBMdisc (1980-2008), CNKI database (1980-2008), Wanfang database (1980-2008), and Chongqing VIP database (1980-2008) were searched. Relevant Chinese periodicals were manually searched as well. All randomized controlled trials comparing Aidi Injection with other treatment methods of NSCLC were included. Two reviewers selected studies, assessed the quality of studies, and extracted the data independently.

 

Fourteen randomized controlled trials were included in the meta-analysis, but unfortunately, the quality of reports of the 14 included studies were poor. Aidi Injection combined with cobalt-60, or navelbine and platinol (NP), showed statistically significant differences in improving the response rate, compared to the use of cobalt-60 alone (P = 0.0002) or NP alone (P = 0.04). However, Aidi Injection combined with etoposide and platinol (EP), taxinol and platinol (TP) or gamma knife showed no significant differences when compared with single use of EP (P=0.60), TP (P=0.16) or gamma knife (P=0.34), respectively. The RR and 95% CI of EP, TP, and gamma knife were 1.17 [0.65, 2.09], 1.27 [0.91, 1.78] and 1.08 [0.92, 1.26] respectively.

 

Six studies indicated that Aidi Injection, combined with NP or gamma knife, could improve quality of life. Six studies showed that Aidi Injection, combined with NP or TP, could improve the bone marrow’s hematopoietic function. The results of the meta-analysis indicate that Aidi Injection may have adjuvant therapeutic effects in the treatment of NSCLC patients. However, sample sizes are small, study quality is poor, and the existence of publication bias had been found. The effects of Aidi Injection need to be confirmed by large multicenter randomized controlled trials (Ma, Duan, Feng, She, Chen & Zhang, 2009).

 

NSCLC; Neo-adjuvant Chemotherapy

Sixty patients, with stage IIIA non-small-cell lung cancer (NSCLC), underwent two courses of bronchial arterial infusion (BAI) chemotherapy, before tumor incision. They were assigned to either the treatment or control group, using a random number table. Thirty patients were allocated to each. An ADI of 100 mL, added into 500 mL of 5% glucose, was given to the patients in the treatment group via intravenous drip. Treatment was once a day, beginning 3 days prior and throughout each of two 14-day courses of chemotherapy.

 

Levels of T-lymphocyte subsets, natural killer cell activity, and interleukin-2 in peripheral blood were measured before and after the treatment. The effective rate in the treatment group was higher than that in the control group (70.0% vs. 56.7%, P < 0.05).

 

Moreover, bone marrow suppression and liver function damage (P < 0.05) was less in the treatment group relative to the control. Cellular immune function was suppressed in NSCLC patients, but was ameliorated after treatment, showing a significant difference when compared to the control group (P < 0.05).

 

ADI could potentially act as an ideal auxiliary drug for patients with stage IIIA NSCLC, receiving BAI neo-adjuvant chemotherapy, before surgical operation. It could enhance the effectiveness of chemotherapy, ameliorate adverse reactions, and elevate patient’s cellular immune function (Sun, Pei, Yin, Wu & Yang, 2010).

 

References

Ma, W.H., Duan, K.N., Feng, M., She, B., Chen, Y., & Zhang, R.M. (2009). Aidi Injection as an adjunct therapy for non-small-cell lung cancer: a systematic review. Journal of Chinese Integrative Medicine, 7(4), 315-324.

Sun, X.F., Pei, Y.T., Yin, Q.W., Wu, M.S., & Yang, G.T. (2010). Application of Aidi injection in the bronchial artery infused neo-adjuvant chemotherapy for stage III A non-small-cell lung cancer before surgical operation. Chinese Journal of Integrative Medicine, 16(6), 537-541.

Wang, D., Chen, Y., Ren, J., Cai, Y., M. Liu, M., & Zhan, Q. (2004). A randomized clinical study on efficacy of Aidi injection combined with chemotherapy in the treatment of advanced non-small-cell lung cancer. Journal of Chinese Integrative Medicine, 7(3), 247-249.

Xu, H.X., Huang, X.E., Li, Y., Li, C.G., & Tang, J.H. (2011). A clinical study on safety and efficacy of Aidi injection combined with chemotherapy. Asian Pacific Journal of Cancer Prevention, 12(9), 2233-2236.

Xu, X.T., Song, Y., Qin, S., Wang, L.L., & Zhou, J.Y. (2012). Radio-sensitization of SHG44 glioma cells by Aidi injection in vitro. Molecular Medicine Reports, 5(6), 1415-1418.

Zhang, H., Zhou, Q.M., Lu, L.L., Du, J., & Su, S.B. (2011). Aidi injection alters the expression profiles of microRNAs in human breast cancer cells. Journal of Traditional Chinese Medicine, 31(1), 10-16.

angiogenesis, Anti-angiogenesis, Anti-angiogenic, anti-tumor, apoptosis, Bladder cancer, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Cip1/p21, Colon Cancer or Colorectal cancer, EGFR, EMT, epidermal growth factor receptor, ERK, ERK1, Fet, Geo, and HCT116, G1, HL-60, HT-29, Induces cell-cycle arrest, iNOS, Lung cancer, metastasis, Nitric Oxide, p21, PKC, S, Silybum marianum, STAT, STAT3, Thyroid cancer, TNF

Silibinin

Cancer:
Lung, leukemia, colorectal, thyroid, breast, bladder

Action: Anti-angiogenesis, EMT, cell-cycle arrest

Cell-cycle Arrest, Colon Cancer

Silibinin, an active constituent of milk thistle (Silybum marianum [(L.) Gaertn.]), has been reported to inhibit proliferation and induce cell-cycle arrest of human colon cancer cells, Fet, Geo, and HCT116 (Hogan et al., 2007). Silibinin Up-regulates the expression of cyclin-dependent kinase inhibitors and induces cell-cycle arrest and apoptosis in human colon carcinoma HT-29 cells (Agarwal et al., 2003). Also in HT-29 cells, treatment with beta-escin, a principal component of horse chestnut, tinduces growth arrest at the G1-S phase together with an induction of Cip1/p21 and an associated reduction in the phosphorylation of retinoblastoma protein (Patlolla et al., 2006).

Lung Cancer

Silibinin also has anti-angiogenic effects on lung adenocarcinomas in vitro, as it strongly decreased both tumor number and tumor size (an anti-tumor effect that correlates with reduced anti-angiogenic activity) (Tyagi et al., 2009). Further, silibinin inhibits mouse lung tumorigenesis in vivo, in part by targeting tumor microenvironment. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) can be pro- or anti-tumorigenic, but in lung cancer cell lines they induce pro-inflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). Accordingly, the mechanism of silibinin action was examined on TNF-α + IFN-γ (hereafter referred as cytokine mixture) elicited signaling in tumor-derived mouse lung epithelial LM2 cells.

Both signal transducers and activators of the transcription (STAT)3 (tyr705 and ser727) and STAT1 (tyr701) were activated within 15 min of cytokine mixture exposure, while STAT1 (ser727) activated after 3 h. Cytokine mixture also activated Erk1/2 and caused an increase in both COX2 and iNOS levels. Pre-treatment of cells with a MEK, NF-κB, and/or epidermal growth factor receptor (EGFR) inhibitor inhibited cytokine mixture-induced activation of Erk1/2, NF-κB, or EGFR, respectively, and strongly decreased phosphorylation of STAT3 and STAT1 and expression of COX2 and iNOS.

Together, the results show that STAT3 and STAT1 could be valuable chemo-preventive and therapeutic targets within the lung tumor microenvironment in addition to being targets within the tumor itself, and that silibinin inhibit their activation as a plausible mechanism of its efficacy against lung cancer (Tyagi et al., 2011).

Leukemia

Silibinin also affects cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Treatment of HL-60 cells with silibinin inhibited cellular proliferation and induced cellular differentiation in a dose-dependent manner.

Silibinin enhanced protein kinase C (PKC) activity and increased protein levels of both PKCα and PKCβ in 1,25-(OH)2D3-treated HL-60 cells. PKC and extracellular signal-regulated kinase (ERK) inhibitors significantly inhibited HL-60 cell differentiation induced by silibinin alone or in combination with 1,25-(OH)2D3, indicating that PKC and ERK may be involved in silibinin-induced HL-60 cell differentiation (Kang et al., 2001).

Thyroid Cancer, Breast Cancer

Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Matrix metalloproteinases (MMPs) play an important role in cancer metastasis, cell migration and invasion. The effects of silibinin were investigated on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. These results revealed that the levels of MMP-9 mRNA and protein expression were significantly increased by TPA but not MMP-2 in TPC-1 and MCF7 cells.

TPA-induced phosphorylation of MEK and ERK was also inhibited by silibinin. Taken together, these results suggest that silibinin suppresses TPA-induced cell migration and MMP-9 expression through the MEK/ERK-dependent pathway in thyroid and breast cancer cells (Oh et al., 2013).

Bladder Cancer

Silibinin induced apoptosis and inhibited proliferation of bladder cancer cells and metastasis. In the present study, Wu et al. (2013) utilized a novel highly metastatic T24-L cell model, and found that silibinin treatment not only resulted in the suppression of cell migration and invasion in vitro, but also decreased bladder cancer lung metastasis and prolonged animal survival in vivo. Inactivation of β-catenin/ZEB1 signaling by silibinin leads to dual-block of EMT and stemness.

Lung Cancer, EMT

Silibinin formulation might facilitate the design of clinical trials to test the administration of silibinin meglumine-containing injections, granules, or beverages in combination with EGFR TKIs in patients with EGFR-mutated NSCLC. Silibinin meglumine notably decreased the overall volumes of NSCLC tumors as efficiently as did the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Concurrent treatment with silibinin meglumine impeded the regrowth of gefitinib-unresponsive tumors, resulting in drastic tumor growth prevention.

Because the epithelial-to-mesenchymal transition (EMT) is required by a multiplicity of mechanisms of resistance to EGFR TKIs, we evaluated the ability of silibinin meglumine to impede the EMT in vitro and in vivo. Silibinin-meglumine efficiently prevented the loss of markers associated with a polarized epithelial phenotype as well as the de novo synthesis of proteins associated with the mesenchymal morphology of transitioning cells (Cuf` et al., 2013).

Breast cancer

Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day.

Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b+ Gr-1+ MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b+Gr-1+ MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment.

Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs.

References

 

Agarwal C, Singh RP, Dhanalakshmi S, et al. (2003). Silibinin Up-regulates the expression of cyclin-dependent kinase inhibitors and causes cell-cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 22:8271–8282.

 

Cufí S, Bonavia R, Vazquez-Martin A, Corominas-Faja B, et al. (2013). Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. Food Chem Toxicol, 60:360-8. doi: 10.1016/j.fct.2013.07.063.

Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS. (2007). Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J Surg Res, 143:58–65.

Kang SN, Lee MH, Kim KM, Cho D, Kim TS. (2001). Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochemical Pharmacology, 61(12):1487–1495

Oh SJ, Jung SP, Han J, et al. (2013). Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Oncol Rep, 29(4):1343-8. doi: 10.3892/or.2013.2252.

Patlolla JM, Raju J, Swamy MV, Rao CV. (2006). Beta-escin inhibits colonic aberrant crypt foci formation in rats and regulates the Cell-cycle growth by inducing p21(waf1/cip1) in colon cancer cells. Mol Cancer Ther, 5:1459–1466.

Tyagi A, Singh RP, Ramasamy K, et al. (2009). Growth Inhibition and Regression of Lung Tumors by Silibinin: Modulation of Angiogenesis by Macrophage-Associated Cytokines and Nuclear Factor-κ B and Signal Transducers and Activators of Transcription 3. Cancer Prev Res, 2(1):74-83

Tyagi A, Agarwal C, Dwyer-Nield LD, et al. (2011). Silibinin modulates TNF‐α and IFN ‐γ mediated signaling to regulate COX2 and iNOS expression in tumorigenic mouse lung epithelial LM2 cells. Molecular Carcinogenesis. doi: 10.1002/mc.20851.

Wu K, Ning Z, Zeng J, et al. (2013). Silibinin inhibits β -catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness. Cell Signal, 25(12):2625-2633. doi: 10.1016/j.cellsig.2013.08.028.

Forghani P, Khorramizadeh MR & Waller EK. (2014) Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer. Cancer Medicine. Volume 3, Issue 2, pages 215–224, April 2014 DOI: 10.1002/cam4.186

ABC, ABCG2, Anti-cancer, anti-tumor, apoptosis, Apoptotic, Bcl-2, BCRP, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, G2/M, Leukemia, MDR, Multi-Drug Resistance, Multi-drug resistance, p53, Pro-apoptotic, radiotherapy

Multi-drug resistance

Multi-drug resistance in cancer chemotherapy refers to the ability of cancer cells to survive from treatment of a wide range of drugs (Meszaros et al., 2009).

In addition to the MDR induced by drugs in early exposure, the MDR cancer cells may subsequently develop cross-resistance to several unexposed and structurally unrelated chemotherapeutic agents (Biedler et al., 1970).

How to tackle the MDR cells in chemotherapy is a pressing issue in cancer treatments. Verapamil was the first known Pgp inhibitor to increase the intracellular concentration of anti-cancer agents in MDR cells by binding to Pgp and inhibiting the Pgp-mediated efflux (Twentyman, 1992). It was believed that anti-cancer drug resistance could be reversed by drug efflux inhibition. Researchers developed and tested a range of Pgp inhibitors to improve the pharmacological effects of chemotherapy in cancer patients (Tsuruo et al., 1981; Stewart et al., 2000; Toppmeyer et al., 2002).

Mechanisms of MDR include decreased uptake of drugs, alterations in cellular pathways and increased active efflux of drugs (Gottesman, 2002; La Porta, 2007; Watson, 1991).

Overexpression of ATP-binding cassette (ABC) transporters is one of the most common mechanisms. Overexpression of the three major ABC transporters, i.e. P-glycoprotein (Pgp), multi-drug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP/ABCG2), is frequently observed in cancer cell lines selected with chemotherapeutic drugs (Szakacs et al., 2006) and critical to clinical drug resistance (Leonard, 2003).

Fractions from 17 clinically used anti-tumor traditional Chinese medicinal herbs were tested for their potential to restore the sensitivity of MCF-7/ADR and A549/Taxol cells to a known anti-neoplastic agent. Five herbs, Curcuma wenyujin, Chrysanthemum indicum, Salvia chinensis, Ligusticum chuanxiong Hort. and Cassia tora L., could sensitize these resistant cancer cells at a non-toxic concentration (10  µg mL–1), and markedly increased doxorubicin accumulation in MCF-7/ADR cells, which necessitates further investigations into the active ingredients of these herbs and their underlying mechanisms (Yang et al., 2011).

Natural sources are a fertile ground to find novel drugs with activity against MDR cancer cells. In some countries, especially China, traditional herbal medicines are often used together with mainstream chemotherapeutic agents. The clinically used traditional Chinese herbs for the treatment of tumor can be classified into four categories based on the theory of Traditional Chinese Medicine (TCM): drugs (CH group) for 'Clearing away Heat and Toxins', drugs (PB group) for 'Promoting Blood Flow to Remove Stasis', drugs for 'Invigoration' and toxic drugs. Drugs for 'Invigoration' have indirect anti-neoplastic action by enhancing an organism's immunity and have been used clinically to minimise radiotherapy- and chemotherapy-induced toxicity (Fu & Chen, 2008; Chai, To, Lin, 2010).

Some of the recent findings on the circumvention of ABC transporters-mediated MDR by various ingredients and extracts of CM and their formulae, based on whether the MDR reversal involved Pgp alteration, are reviewed below.

Saponins

Ginsenosides are the major active components from Panax ginseng (Renshen). Ginsenosides are mainly triterpenoid dammarane derivatives. Several ginsenosides, namely Rg1, Rg3, Re, Rc and Rd inhibited drug efflux (Kim et al., 2003). A combination of purified saponins containing Rb1, Rb2, Rc, Rd, Re and Rg1 reversed MDR whereas individual ginsenosides did not produce any effect (Park et al., 2006). Ginsenosides reversed MDR of several chemotherapeutic drugs such as homoharringtonine, cytarabine, doxorubicin and etoposide in K562/VCR and in a dose-dependent manner in K562/DOX (Gao et al., 2004).

Pgp expression decreased but bcl-2 expression remained the same (Wang, 2003). Rb1 reversed MDR of harringtonolide and vincristine in K562/HHT and HL60/VCR cell lines respectively (Shi et al. , 2005).

Panax notoginseng (Sanqi) total saponins reversed MDR of doxorubicin in MCF-7/DOX and K562/VCR cell lines. The mechanism may be related to the decrease of Pgp expression (Si & Tien, 2005; Liu, Liu, & Fang, 2008).

Rg3, one of the active ginsenosides from Panax ginseng, restored the sensitivity of resistant KBV20 cell line to various anti-cancer drugs, including vincristine, doxorubicin, etoposide and colchicine in a time-and dose-dependent manner. This ginsenoside competitively inhibited the binding of substrate drugs to Pgp and its binding affinity to Pgp was remarkably higher than that of verapamil. In contrast to the dose-dependent effects in vitro, Rg3 increased animal life span in an in vivo MDR model in a dose-independent manner (Kim et al., 2003).

Flavonoids

Quercetin is one of the most widely distributed flavonoids in natural products including Chinese medicinal herbs such as Sophora japonica (Huai). Quercetin inhibited the binding of heat shock factor at the MDR1 promoter, thereby decreasing MDR1 transcription and reducing Pgp expression (Kim et al., 1998). Quercetin also inhibited the overexpression of Pgp mediated by arsenite (Kioka et al., 1992). In HL-60/DOX and K562/DOX cell lines, quercetin enhanced the anti-cancer sensitivity to daunorubicin and decreased Pgp expression (Cai et al., 2004; Cai et al., 2005). MDR reversal effect of quercetin was probably mediated by its action on mitochondrial membrane potential and the induction of apoptosis. Furthermore, quercetin derivatives rather than quercetin itself reversed MDR (Kothan et al., 2004). Quercetin increased the sensitivity of Pgp-overexpressing KBV1 cell line towards vinblastine and paclitaxel in a dose-dependent manner. Among many active flavonoids, quercetin was less potent than kaempferol but more effective than genistein and daidzein in reversing MDR. Genistein and daidzein had no effect on Pgp expression (Limtrakul, Khantamat, & Pintha, 2005).

Although quercetin may be a potential MDR reversing agent, lethal drug-drug interaction between quercetin and digoxin has been reported. Quercetin (40 mg/kg) elevated the peak blood concentration of digoxin and caused sudden death of tested animals (Wang et al., 2004).

Paeonol is a weak calcium channel blocker isolated from the root of Paeonia suffruticosa (Mudan). In K562/DOX cell line, paeonol showed positive MDR reversal effect towards doxorubicin, daunorubicin, vincristine and vinblastine without modulating Pgp expression [100]. In parental K562 cells, paeonol induced apoptosis in a time-and dose-dependent manner (Sun et al., 2004).

Curcumin, the major component in Curcuma longa (Jianghuang), inhibited the transport activity of all three major ABC transporters, i.e. Pgp, MRP1 and ABCG2 (Ganta & Amiji, 2009). Curcumin reversed MDR of doxorubicin or daunorubicin in K562/DOX cell line and decreased Pgp expression in a time-dependent manner (Chang et al., 2006). Curcumin enhanced the sensitivity to vincristine by the inhibition of Pgp in SGC7901/VCR cell line (Tang et al., 2005). Moreover, curcumin was useful in reversing MDR associated with a decrease in bcl-2 and survivin expression but an increase in caspase-3 expression in COC1/DDP cell line (Ying et al., 2007). The cytotoxicity of vincristine and paclitaxel were also partially restored by curcumin in resistant KBV20C cell line (Um et al., 2008). Curcumin derivatives reversed MDR by inhibiting Pgp efflux (Um et al., 2008).

A chlorine substituent at the meta-or para-position on benzamide improved MDR reversal (Um et al., 2008). Bisdemethoxycurcumin modified from curcumin resulted in greater inhibition of Pgp expression (Limtrakul, Anuchapreeda, & Buddhasukh, 2004). Tetrahydrocurcumin, the major metabolite of curcumin, inhibited all three major ABC transporters (Limtrakul et al., 2007). Curcumin induced atypical and caspase-independent cell death in MDR cells (Piwocka, Bielak-Mijewska, & Sikora, 2002). In leukaemic cells collected from 78 childhood leukaemia patients, curcumin reduced Pgp expression (Anuchapreeda et al., 2006). A specialized nanoemulsion of curcumin is better than conventional solution form drugs in enhancing the efficiency of drug delivery into the cells, down-regulating Pgp expression, inhibiting the NFκB pathway and promoting apoptotic response (Choi et al., 2008).

Other Compounds

Schizandrins, the active constituents of Schisandra chinensis (Wuweizi), were investigated for their MDR reversal effects. Schizandrin A was the most potent in reversing MDR by enhancing apoptosis and down-regulating Pgp and total protein kinase C expression. The crude extract of Schisandra chinensis reversed the resistance against vincristine in vivo (Huang et al., 2008). Deoxyschizandrin and γ-schizandrin, among the nine dibenzo[a,c]cyclooctadiene lignans examined, enhanced intracellular drug concentration and induced cell-cycle arrest at the G2/M phase when combined with sub-toxic dosages of doxorubicin (Slaninová et al., 2009). Gomisin A, on the other hand, altered Pgp-substrate interaction by binding to Pgp simultaneously with substrates (Wan et al., 2006).

Formulae – injections (See Injectables)

'Shengmai Injection', consisting of Panax ginseng and Ophiopogon japonicus (Maidong), down-regulated Pgp expression in peripheral blood lymphocyte membrane. When used together with oxaliplatin, 5-fluorouracil or folinic acid, the injection prolonged the survival rate of colon cancer patients (Cao et al., 2005). The injection also enhanced the efficacy of tamoxifen and nifedipine in combination therapy (Lin et al., 2002).

'KLT Injection' consisting of the extract of Coix lacryma-jobi (Yiyi) enhanced the anti-cancer activities of paclitaxel and docetaxel and reversed MDR in a dose-dependent manner (Dong, Zheng, & Lu, 2002).

Formulae – powders

'Shenghe Powder', consisting of Panax ginseng, Scorophularia ningpoensis (Xuanshen) and Atractylodes macrocephala (Baizhu), increased the intracellular concentration of vincristine in resistant SGC-7901/VCR cell line, possibly due to the induction of apoptosis and down-regulation of Pgp and bcl-2 expression (Wang et al., 2007).

'Modified Sanwubai Powder', consisting of herbs such as Croton tiglium (Badou), Platycodon grandiflorum (Jiegeng) and Fritillaria thunbergii, induced apoptosis in SGC-7901 cell line and down-regulated the gene expressions of p53, bcl-2, rasP21CD44 and Pgp (Xu et al., 2005).

Formulae – others

Three herbal extracts used to treat diseases other than cancer, namely Ams-11, Fw-13 and Tul-17, greatly enhanced the efficacy of vincristine both in vitro and in vivo and reversed MDR in a dose-dependent manner. Tul-17 inhibited Pgp expression (Qu et al., 2006).

Oil emulsion from Brucea javanica (Yadanzi) reversed MDR when used together with other chemotherapeutic drugs such as vincristine, doxorubicin, cisplatin, mitomycin C, 5-fluorouracil or etoposide, probably due to down-regulation of Pgp expression or inhibition of TOPO II or both (Yu, Wu, Zhang, 2001).

'Sangeng Mixture Decoction', consisting of Reynoutria japonica (Huzhang), Actinidia arguta (Mihouligen) and Geum aleppicum (Shuiyangmeigen), reversed MDR of doxorubicin via down-regulation of Pgp expression (Feng et al., 2003).

FFTLG, a formula containing Actinidia arguta, reversed MDR in K562/DOX cell line by increasing the intracellular doxorubicin concentration (Guo, Xie, Feng, 2002).

R1, consisting of Ligusticum chuanxiong, Curcuma longa and Millettia dielsiana (Jixueteng), enhanced the anti-cancer activities of doxorubicin in MCF-7/DOX via down-regulation of Pgp expression (Chen et al., 2003; Lin, 2007).

Formulae

'Ganli Injection', consisting of matrine and tetramethylpyazine hydrochloride, reversed MDR by increasing the sensitivity of 5-fluorouracil and the intracellular concentration of doxorubicin in BEL-7402/5-FU cell line (Gu et al., 2007).

'Bushen Huayu Jiedu Formula', consisting of Cinnamomum cassia (Rougui), Psoralea corylifolia (Buguzhi) and Rheum palmatum, was tested in A549/DDP cell line and S180 tumor-bearing mice. In vitro, the formula significantly increased the intracellular concentration of cisplatin at high doses and inhibited the activity of calcium channel and LRP-56 expression at both high and low doses. In vivo, the formula improved the serum concentration, reduced the inflow and the release of Ca2+ and inhibited the LRP gene expression (Cao et al., 2004; Cao et al., 2008).

Four CM formulae, namely Glycyrrhiza glabra (GLYC), Hedyotis diffusa (OLEN), a formula consisting of 15 herbs including Cistanche deserticola (Roucongrong), Rabdosia rubescens (Donglingcao) and Zanthoxylum nitidum (Liangmianzhen) (SPES), and a formula consisting of eight herbs including Serenoa repens (Juyezhong), Scutellaria baicalensis (Huangqin), Panax ginseng and Glycyrrhiza glabra (PC-SPES) were cytotoxic to cancer cell lines in a dose-dependent manner. SPES, PC-SPES, OLEN decreased the bcl-2 gene expression and were pro-apoptotic, while GLYC was pro-necrotic without altering the over-expression of bcl-2 in MDR cells. Furthermore, OLEN, SPES and PC-SPES exhibited similar pharmacological effects to etoposide and vincristine (Sadava et al., 2002).

References

Anuchapreeda S, Thanarattanakorn P, Sittipreechacharn S, et al. (2006). Inhibitory effect of curcumin on MDR1 gene expression in patient leukemic cells. Arch Pharm Res, 29(10):866-873

Biedler JL, Riehm H. (1970). Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res, 30:1174-1184.

Cai X, Chen FY, Han JY, et al. (2004). Restorative effect of quercetin on subcellular distribution of daunorubicin in Multi-drug-resistant leukemia cell lines K562/ADM and HL-60/ADM. Chin J Cancer, 23(12):1611-1615.

Cai X, Chen FY, Han JY, et al. (2005). Reversal of Multi-drug resistance of HL-60 adriamycin resistant leukemia cell line by quercetin and its mechanisms. Chin J Oncol, 27(6):326-329.

Cao CM, Ding XD, Wang XH, Liu P. (2005). Clinical study of shengmai injection in its reversing MDR effect in late phase colon carcinoma patients. Shandong J Tradit Chin Med, 24(9):529-532.

Cao Y, Zhang D, Zheng GJ, Yang Y, Zhang J. (2004). Study on drug resistance reversion and mechanism of bushen huayu jiedu formula in lung cancer cells of drug resistance. Shandong J Trad Chin Med, 23(2):100-104.

Cao Y, Xia Q, Meng H, Zhong A. (2008). Pharmacological effects of serum containing chinese medicine bushen huayu jiedu compound recipe in lung cancer drug-resistance cells. Chin J Integr Med, 14(1):46-50.

Chang HY, Pan KL, Ma FC, et al. (2006). The study on reversing mechanism of Multi-drug resistance of K562/DOX cell line by curcumin and erythromycin. Chin J Hem, 27(4):254-258.

Choi BH, Kim CG, Lim Y, Shin SY, Lee YH. (2008). Curcumin down-regulates the Multi-drug resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway. Cancer Lett, 259(1):111-118.

Chen XY, Liu JT. (2003). Study on tumor cells' Multi-drug resistance and its reversion by Chinese herbs. J Chin Integr Med, 1(3):221-225.

Dong QH, Zheng S, Lu QH. (2002). Study on the effect of Kanglaite injection on MDR human leukemia cell lines. J Pract Oncol, 17(1):24-26.

Feng ZQ, Guo Y, Zhu NX, et al. (2003). The experiment of SANGENG mixture decoction on reversing Multi-drug resistance. Bull Chin Cancer, 12(6):370-371.

Fu YL and Chen T. (2008). Research of traditional Chinese medicine in the treatment of leukemia: current status. Journal of Chinese Integrative Medicine, 6: 867–872.

Ganta S, Amiji M. (2009). Coadministration of paclitaxel and curcumin in nanoemulsion formulations To overcome Multi-drug resistance in tumor cells. Mol Pharm, 6(3):928-939.

Gao RL, Lin XJ, Qian XD, Chen XH, Niu YP. (2004). Effect of ginsenosides and panaxatriol extracted from ginseng on inhibition of proliferation, inducing apoptosis and cytotoxic drug sensitivity in leukemic cells. J Chin Med Res, 4(2):97-99.

Gottesman MM. (2002). Mechanisms of cancer drug resistance. Annu Rev Med, 53:615-617.

Gu W, Zhai XF, Zhang YN, Ling CQ. (2007). In vitro study of Ganli injection on reversing acquired Multi-drug resistance of human hepatocellular carcinoma. Chin Trad Herbal Drugs, 38(6):871-874.

Guo Y, Xie CS, Feng ZQ. (2002). The study of effects on accumulation and efflux of intracellular adrimycine with FFTLG for Multi-drug-resistant cell lines K562/ADR and K562/VCR in vitro. Chin J Mod Appl Pharm, 19(4):268-272.

Huang M, Jin J, Sun H, Liu GT. (2008). Reversal of P-glycoprotein-mediated Multi-drug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae. Cancer Chemother Pharmacol, 62(6):1015-1026.

Kim SH, Yeo GS, Lim YS, et al. (1998). Suppression of Multi-drug resistance via inhibition of heat shock factor by quercetin in MDR cells. Exp Mol Med, 30(2):87-92.

Kim SW, Kwon HY, Chi DW, (2003). Reversal of P-glycoprotein-mediated Multi-drug resistance by ginsenoside Rg3. Biochem Pharmacol, 65(1):75-82.

Kioka N, Hosokawa N, Komano T, et al. (1992). Quercetin, a bioflavonoid, inhibits the increase of human Multi-drug resistance gene (MDR1) expression caused by arsenite. FEBS Lett, 301(3):307-309.

Kothan S, Dechsupa S, Leger G, et al. (2004). Spontaneous mitochondrial membrane potential change during apoptotic induction by quercetin in K562 and K562/adr cells. Can J Physiol Pharm, 82(12):1084-1090.

La Porta CAM. (2007). Drug resistance in melanoma: new perspectives. Curr Med Chem, 14(4):387-91.

Leonard GD, Fojo T, Bates SE. (2003). The role of ABC transporters in clinical practice. Oncologist, 8(5):411-424.

Li Y, Wang ZZ, Yu TF (2005). In vitro study on the reversal of Multi-drug resistance (MDR) in HL60/VCR cell line with ginsenoside – Rb1. J Radioimmunol, 18(5):362-365.

Limtrakul P, Anuchapreeda S, Buddhasukh D. (2004). Modulation of human Multi-drug resistance MDR-1 gene by natural curcuminoids. BMC Cancer, 4:13.

Limtrakul P, Chearwae W, Shukla S, Phisalphong C, Ambudkar SV. (2007). Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and Multi-drug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. Mol Cell Biochem, 296(1-2):85-95.

Limtrakul P, Khantamat O, Pintha K. (2005). Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J Chemother, 17(1):86-95.

Lin SY, Qin ZQ, Xu YF, Wu LC, Liu LM. (2002). Significance of combination shenmal injection, tamoxifen and nifedipine in treatment stage IV non-small-cell lung cancer. Chin J Cancer Prev Treat, 9(4):454-455.

Lin GF. (2007). Current situation in studying the reversing effect in Multi-drug-resistant in cancer cells by TCM. China Pharm, 16(10):63-64.

Liu LL, Liu YE, Fang GT. (2008). Reversal effect of Panax notoginseng saponins on Multi-drug resistance breast cancer cell MCF/ADM. Lishizhen Med Materia Med Res, 19(4):954-956.

Meszaros A, Balogh G. (2009). Multiple Drug Resistance. Gazelle Distribution, Lancaster, UK.

Park JD, Kim DS, Kwon HY, et al. (1996). Effects of ginseng saponin on modulation of Multi-drug resistance. Arch Pharm Res, 19(3):213-218.

Wang L. (2003). Reversing drug resistance of human erythroleukemia cell line K562/DOX on DOX by total saponings Panax ginseng. J Chongqing Med Univ, 28(4):424-427, 435.

Piwocka K, Bielak-Mijewska A, Sikora E. (2002). Curcumin induces caspase-3-independent apoptosis in human Multi-drug-resistant cells. Ann N Y Acad Sci, 973:250-254.

Qu Y, Liu SQ, Zhang XB, et al. (2006). Reversal of P-glycoprotein mediated Multi-drug resistance by traditional Chinese medicines. Nat Prod Res Dev, 18(6):932-936.

Sadava D, Ahn J, Zhan M, et al. (2002). Effects of four Chinese herbal extracts on drug-sensitive and Multi-drug-resistant small-cell lung carcinoma cells. Cancer Chemother Pharmacol, 49(4):261-266.

Shi XK, Zhang YJ, Zhao CJ. (1999). The reverse effects of ginseng saponin Rb1 on Multi-drug resistance of human leukemic cell line K562/HHT in vitro. Acta Acad Med Militaris Tertiae, 21(11):825-827.

Si YQ, Tien TD (2005). The Multi-drug-resistant reversing effect of total Panax notoginseng saponins studied in K562/VCR cell line. Chin J Tradit Med Sci Technol, 12(5):292-294.

Slaninová I, Brezinová L, Koubíková L, Slanina J. (2009). Dibenzocyclooctadiene lignans overcome drug resistance in lung cancer cells–study of structure-activity relationship. Toxicol In Vitro, 23(6):1047-1054.

Stewart A, Steiner J, Mellows G, et al. (2000). Phase I trial of XR9576 in healthy volunteers demonstrates modulation of Pglycoprotein in CD56+ lymphocytes after oral and intravenous administration. Clin Cancer Res, 6(11):4186-4191.

Sun GP, Wang H, Shen YX, et al. (2004). Study on effects of paeonol in inhibiting growth of K562 and inducing its apoptosis. Chin Pharmacol Bull, 20(5):550-552.

Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. (2006). Targeting Multi-drug resistance in cancer. Nat Rev Drug Discov, 5(3):219-234.

Tang XQ, Bi H, Feng JQ, Cao JG. (2005). Effect of curcumin on Multi-drug resistance in resistant human gastric carcinoma cell line SGC7901/VCR. Acta Pharmacol Sin, 26(8):1009-1016.

Toppmeyer D, Seidman AD, Pollak M, et al. (2002). Safety and efficacy of the Multi-drug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel. Clin Cancer Res, 8(3):670-678.

Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. (1981). Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res, 41(5):1967-1972.

Twentyman PR. (1992). Cyclosporins as drug resistance modifiers. Biochem Pharmacol, 43(1):109-117.

Um Y, Cho S, Woo HB, et al. (2008). Synthesis of curcumin mimics with Multi-drug resistance reversal activities. Bioorg Med Chem, 16(7):3608-3615.

Wan CK, Zhu GY, Shen XL, et al. (2006). Gomisin A alters substrate interaction and reverses P-glycoprotein-mediated Multi-drug resistance in HepG2-DR cells. Biochem Pharmacol, 72(7):824-837.

Wang Y, Chao PL, Hsiu SL, Wen K, Hou Y. (2004). Lethal quercetin-digoxin interaction in pigs. Life Sci, 74(10):1191-1197.

Wang J, Xia Y, Wang H, Hou Z. (2007). Chinese herbs of Shenghe powder reverse Multi-drug resistance of gastric carcinoma SGC-7901. Integr Cancer Ther, 6(4):400-404

Watson JV. (1991). Introduction to Flow Cytometry Cambridge. Cambridge University Press, Cambridge, UK.

Xu L, Wang MY, Xu DQ, Zhou CX. (2005). Experimental study on modified 'Sanwubai Powder' in affecting multi-drug resistance gene expression of tumor. Shanghai J Tradit Chin Med, 39(8):59-60.

Yang L, Wei DD, Chen Z, et al. (2011). Reversal effects of traditional Chinese herbs on Multi-drug resistance in cancer cells. Natural Product Research (Formerly Natural Product Letters), 25(19):1885-1889. doi: 10.1080/14786419.2010.541395

Ying HC, Zhang SL, Lv J. (2007). Drug-resistant reversing effect of curcumin on COC1/DDP and its mechanism. J Mod Oncol, 15(5):604-607.

Yu LF, Wu YL, Zhang YP. (2001). Reversal of drug resistance in the vincristine-resistant human gastric cancer cell lines MKN28/VCR by emulsion of seminal oil of Brucea Javanica. World Chin J Digestol, 9(4):376-378.

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, Anti-tumoral, Anti-tumoral., AP-1, Apoptotic, Breast cancer, c-Jun, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, Chemo-preventive agent, Colon Cancer or Colorectal cancer, COX-2, COX-2 inhibitor, ERK1, inflammation, Lung cancer, Melanoma, p38, PKC

Carnosol

Cancer: Breast, prostate, skin, colon, leukemia, stomach

Action: Anti-inflammatrory, anti-angiogenic

Carnosol is found in certain Mediterranean meats, fruits, vegetables, and olive oil. In particular, it is sourced from rosemary (Rosmarinus officinalis (L.)) and desert sage (Salvia pachyphylla (Epling ex Munz)).

Prostate Cancer, Breast Cancer, Skin Cancer, Colon Cancer, Leukemia

One agent, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals.

This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent (Johnson, 2011).

Literature evidence from animal and cell culture studies demonstrates the anti-cancer potential of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid to suppress the development of tumors in several organs including the colon, breast, liver, stomach, as well as melanoma and leukemia cells (Ngo et al., 2011).

Anti-inflammatory

Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anti-cancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity.

Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms (Subbaramaiah, 2002).

Breast Cancer

Two rosemary components, carnosol and ursolic acid, appear to be partly responsible for the anti-tumorigenic activity of rosemary. Supplementation of diets for 2 weeks with rosemary extract (0.5% by wt) but not carnosol (1.0%) or ursolic acid (0.5%) resulted in a significant decrease in the in vivo formation of rat mammary DMBA-DNA adducts, compared to controls. When injected intraperitoneally (i.p.) for 5 days at 200 mg/kg body wt, rosemary and carnosol, but not ursolic acid, significantly inhibited mammary adduct formation by 44% and 40%, respectively, compared to controls. Injection of this dose of rosemary and carnosol was associated with a significant 74% and 65% decrease, respectively, in the number of DMBA-induced mammary adenocarcinomas per rat, compared to controls. Ursolic acid injection had no effect on mammary tumorigenesis.

Therefore, carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent (Singletary et al., 1996).

Anti-angiogenic

The anti-angiogenic activity of carnosol and carnosic acid could contribute to the chemo-preventive, anti-tumoral and anti-metastatic activities of rosemary extracts and suggests that there is potential in the treatment of other angiogenesis-related malignancies (L-pez-JimŽnez et al., 2013).

References:

Johnson JJ. (2011). Carnosol: A promising anti-cancer and anti-inflammatory agent. Cancer Letters, 305(1):1-7. doi:10.1016/j.canlet.2011.02.005.


L-pez-JimŽnez A, Garc'a-Caballero M, Medina Mç, Quesada AR. (2013). Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary. Eur J Nutr, 52(1):85-95. doi: 10.1007/s00394-011-0289-x.


Ngo SN, Williams DB, Head RJ. (2011). Rosemary and cancer prevention: preclinical perspectives. Crit Rev Food Sci Nutr, 51(10):946-54. doi: 10.1080/10408398.2010.490883.


Singletary K, MacDonald C & Wallig M. (1996). Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Letters, 104(1):43-8. doi: 10.1016/0304-3835(96)04227-9


Subbaramaiah K, Cole PA, Dannenberg AJ. (2002). Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms. Cancer Res, 62:2522

Chapter 5 Cancer Tables isolates, Colon Cancer or Colorectal cancer

Colon/Colorectal Cancer

Colorectal cancer is also known as colon cancer, rectal cancer, or bowel cancer, and colon and rectal tumors are genetically the same cancer. Cancers that are confined within the wall of the colon are often curable with surgery while cancer that has spread widely around the body is usually not curable and management then focuses on extending the person’s life via chemotherapy and improving quality of life. Screening is effective at decreasing the chance of dying from colorectal cancer and is recommended starting at the age of 50 and continuing until a person is 75 years old. Localized bowel cancer is usually diagnosed through sigmoidoscopy or colonoscopy.

The following stages are used for colon cancer:

In stage 0, abnormal cells are found in the mucosa (innermost layer) of the colon wall. These abnormal cells may become cancer and spread. Stage 0 is also called carcinoma in situ.

In stage I, cancer has formed in the mucosa (innermost layer) of the colon wall and has spread to the submucosa (layer of tissue under the mucosa). Cancer may have spread to the muscle layer of the colon wall.

Stage II colon cancer is divided into stage IIA, stage IIB, and stage IIC.

• Stage IIA: Cancer has spread through the muscle layer of the colon wall to the serosa (outermost layer) of the colon wall.

• Stage IIB: Cancer has spread through the serosa (outermost layer) of the colon wall but has not spread to nearby organs.

• Stage IIC: Cancer has spread through the serosa (outermost layer) of the colon wall to nearby organs.

In stage IIIA: Cancer may have spread through the mucosa (innermost layer) of the colon wall to the submucosa (layer of tissue under the mucosa) and may have spread to the muscle layer of the colon wall. Cancer has spread to at least one but not more than 3 nearby lymph nodes or cancer cells have formed in tissues near the lymph nodes; or

• Cancer has spread through the mucosa (innermost layer) of the colon wall to the submucosa (layer of tissue under the mucosa). Cancer has spread to at least 4 but not more than 6 nearby lymph nodes.

In stage IIIB: Cancer has spread through the muscle layer of the colon wall to the serosa (outermost layer) of the colon wall or has spread through the serosa but not to nearby organs. Cancer has spread to at least one but not more than 3 nearby lymph nodes or cancer cells have formed in tissues near the lymph nodes; or

• Cancer has spread to the muscle layer of the colon wall or to the serosa (outermost layer) of the colon wall. Cancer has spread to at least 4 but not more than 6 nearby lymph nodes; or

• Cancer has spread through the mucosa (innermost layer) of the colon wall to the submucosa (layer of tissue under the mucosa) and may have spread to the muscle layer of the colon wall. Cancer has spread to 7 or more nearby lymph nodes.

In stage IIIC: Cancer has spread through the serosa (outermost layer) of the colon wall but has not spread to nearby organs. Cancer has spread to at least 4 but not more than 6 nearby lymph nodes; or

• Cancer has spread through the muscle layer of the colon wall to the serosa (outermost layer) of the colon wall or has spread through the serosa but has not spread to nearby organs. Cancer has spread to 7 or more nearby lymph nodes; or

• Cancer has spread through the serosa (outermost layer) of the colon wall and has spread to nearby organs. Cancer has spread to one or more nearby lymph nodes or cancer cells have formed in tissues near the lymph nodes.

Stage IV colon cancer is divided into stage IVA and stage IVB.

• Stage IVA: Cancer may have spread through the colon wall and may have spread to nearby organs or lymph nodes. Cancer has spread to one organ that is not near the colon, such as the liver, lung, or ovary, or to a distant lymph node.

• Stage IVB: Cancer may have spread through the colon wall and may have spread to nearby organs or lymph nodes. Cancer has spread to more than one organ that is not near the colon or into the lining of the abdominal wall.

Sources

Cunningham, D., Atkin, W., Lenz, H.J, et al. (2010) Colorectal cancer. Lancet 375 (9719): 1030–47. doi:10.1016/S0140-6736(10)60353-4. PMID 20304247. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960353-4/fulltext

NCI. (2013) Stages of Colon Cancer. http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient/page2

 

Colon/Colorectal Cancer

Cell Type

Herb Source(s)

Isolate

Refs

advanced or recurrent

brown seaweed

Fucoidan

Ikeguchi et al., 2011

advanced and metastatic

Astragalus membranaceus

Formononetin

Auyeung et al., 2012

C26

Dioscorea zingiberensis

Deltonin

Tong et al., 2011

C26

Dioscorea zingiberensis

Deltonin

Shu et al., 2011

Caco-2

Camellia sinensis

EGCG

Chen et al., 1998

Caco-2,HCT-116

Vaccinium genus,

Piceatannol

Wolter et al., 2002

carcinogenesis

Anemarrhena asphodeloides

Mangiferin

Yoshimi et al., 2001

Colo-205

Solanum incanum

Solanum indicum saponins

Gao et al., 2011

CT-26

species of blister beetles, \including Mylabris phalerata and Lytta vesicatoria

Norcantharidin

Chen et al., 2009

CT-26

Stephania tetrandra

Tetrandrine

Wu et al., 2010

Fet, Geo, and HCT116

Silybum marianum

Silibinin

Hogan et al., 2007

HCT-116

Betula pubescens,
Ziziphus mauritiana,

Prunella vulgaris,

Triphyophyllum peltatum and Ancistrocladus heyneanus, etc.

Betulinic acid

Aisha, 2013

HCT-116

Pinus genus

Pinosylvin

Park et al., 2013

HCT116

Citrus aurantium

Naringin

Yoon et al., 2013

HCT116

Citrus aurantium

Naringin

Woo et al., 2012

HCT116

Scutellaria rivularis

Scutellaria baicalensis

Wogonin

Wang et al., 2013

HCT-116

Curcuma zedoaria

Alismol

Syed Abdul Rahman, Abdul Wahab, & Abd Malek, 2013

HCT-116

Curcuma zedoaria

Curzerenone

Syed Abdul Rahman, Abdul Wahab, & Abd Malek, 2013

HCT-116

Panax genus

Ginsenosides

Kim at al., 2010

HCT-116

Panax genus

Ginsenosides

Kim et al., 2013 b

HCT-116

Magnolia officinalis

Magnolol

Park et al., 2012

HCT-116

Dendrobrium loddigesii

Moscatilin

Chen et al., 2008

HCT-116

Sanguinaria canadensis

Sanguinarine

Han, Kim, Yoo, & Choi, 2013

HCT-116

Nigella sativa

Thymoquinone

Gali-Muhtasib et al., 2004

HCT-116,SW-480

Alkanna tinctoria

Angelylalkannin

Huu et al., 2013

HCT-116,SW-480

Camellia sinensis

EGCG

Du et al., 2013

HCT-116,SW-480

Panax genus

Ginsenosides

Wang et al., 2006

HCT-116,SW-480

Panax genus

Ginsenosides

Du et al., 2013

HCT-116,SW-480

Panax ginseng

Panaxadiol

Du et al., 2013

HCT-116,SW-480

Alkanna cappadocica

Alkannin

Huu et al., 2013

HCT-15

brown seaweed

Fucoidan

Hyun et al., 2009

HT29

Scutellaria barbata

Ent-clerodane diterpenoids

Qu et al., 2010

HT29

Paeonia suffruticosa

Paeoniflorin

Wang et al., 2012

HT29

Nigella sativa

Thymoquinone

Attoub et al., 2012

HT-29

Alkanna cappadocica

5-O-methyl-11-O-acetylalkannin

Sevimli-Gur et al., 2010

HT-29

Boswellia carterri Birdw,

Boswellia serrata

Acetyl-keto-beta-boswellic acid (AKBA)

Liu et al., 2002

HT-29

Scutellaria radix,
Scutellaria rivularis,

Scutellaria baicalensis,

Scutellaria lateriflora

Baicalein

Kim et al., 2012

HT-29

Betula platyphylla,

Betula X caerulea,

Betula cordifolia,

Betula papyrifera,

Betula populifolia,

Dillenia indica

Betulin

Rzeski, 2009

HT-29

Trigonella foenum-graecum

Diosgenin

Raju et al., 2004

HT-29

Hippophae rhamnoides

Isorhamnetin

Zhu et al., 2005

HT-29

many plants and foods, including Terminalia chebula,

Prunella vulgaris

and Perilla frutescens

Luteolin

Lim et al., 2007

HT-29

Citrus aurantium

Naringin

Karimi et al., 2012

HT-29

Paeonia suffruticosa

Paenol

Ye et al., 2009

HT-29

Pueraria lobata

Puerarin

Li, et al., 2006

HT-29

Panax ginseng

RG3

Yuan et al., 2010

HT-29

Silybum marianum

Silibinin

Agarwal et al., 2003

HT-29

Silybum marianum

Silibinin

Patlolla et al., 2006

HT-29

tomato

Tomatine/Tomatidine

Friedman et al., 2009

HT-29

Rosmarinus officinalis,

Salvia officinalis,

Prunella vulgaris,

Psychotria serpens

Hyptis capitata

Ursolic acid

Andersson et al., 2003

HT-29

Rosmarinus officinalis,

Salvia officinalis,

Prunella vulgaris,

Psychotria serpens

Hyptis capitata

Ursolic acid

Lin et al., 2013

HT-29

Scutellaria rivularis

Scutellaria baicalensis

Wogonin

Kim et al., 2012

HT-29, Caco-2

Vaccinium arctostaphylos

Blueberin

Yi, 2005

HT-29

Scutellaria baicalensis, Passiflora caerulea, Passiflora incarnate, honey, and propolis

Chrysin

Zheng et al., 2003

KM12L4

soy, barley, wheat, and rye,

including Glycine max,

Hordeum vulgare,

Triticum (L.) genus
and Secale cereale L

Lunasin

Dia et al., 2011

Lovo

Andrographis paniculata

Andrographolide

Shi, 2009

LS1034

Rheum palmatum.,

Senna obtusifolia,

Fallopia japonica, Kalimeris indica, Ventilago madraspatana, Rumex nepalensis, Fallopia multiflora, Cassia occidentalis,

Senna siamea,

Acalypha australis

Emodin

Ma et al., 2012

RKO

Magnolia genus

Honokiol

Hirano et al., 1994;

Wang et al., 2004;

Hibasami et al., 1998;

Konoshima et al., 1991;

Yang et al., 2002;

Kong et al., 2005

SW1116 cells

Rabdosia rubescens

Oridonin

Gao et al., 2012

SW480

Cortex periplocae

Periplocin

Du et al., 2009

SW480

Sophora Flavescen

Sophoridine

Wang et al., 2010

SW480

Sophora Flavescen

Sophoridine

Liang et al., 2012

SW480, DLD-1, LS174T

various fruits, vegetables,
and herbs

Apigenin

Chunhua, 2013

SW480, SW620

Cordyceps sinensis

Cordycepin

He et al., 2010

SW620

 

Artemisunate

Fan, Zhang, Yao, & Li, 2008

SW620

Sophora Flavescen

Sophoridine

Liang et al., 2008

Non specific

Camptotheca acuminate

10-hydroxycamptothecin (HCPT)

Ping et al., 2006

Non specific

Boswellia carterri Birdw,

Boswellia serrata

Acetyl-keto-beta-boswellic acid (AKBA)

Liu et al., 2006

Non specific

Boswellia carterri Birdw,

Boswellia serrata

Acetyl-keto-beta-boswellic acid (AKBA)

Yuan et al., 2013

Non specific

Berberis amurensis

Berberine

Wu et al., 2012

Non specific

Betula platyphylla,

Betula X caerulea,

Betula cordifolia,

Betula papyrifera,

Betula populifolia,

Dillenia indica

Betulin

Rzeski, 2009

Non specific

 

Carnosic acid

Ngo et al., 2011

Non specific

Rosmarinus officinalis

Salvia pachyphylla

Carnosol

Johnson, 2011

Non specific

Rosmarinus officinalis

Salvia pachyphylla

Carnosol

Ngo et al., 2011

Non specific

Vitex rotundifolia

Casticin

Tang et al., 2013

Non specific

Curcuma longa

Curcumin

Kawamori et al., 1999

Non specific

berries, walnuts, pecans, pomegranate, cranberries,

and longan

Ellagic acid

Losso et al., 2004; Larrosa et al., 2006; Malik et al., 2011

Non specific

Syzygium aromaticum

Eugenol

Jaganathan et al., 2011

Non specific

Panax genus

Ginsenosides

Li et al., 2009

Non specific

Magnolia genus

Honokiol

Cheng et al., 2011

Non specific

Magnolia genus

Honokiol

He et al., 2011

Non specific

Hippophae rhamnoides

Isorhamnetin

Saud et al., 2013

Non specific

soy, barley, wheat, and rye,

including Glycine max,

Hordeum vulgare,

Triticum (L.) genus and
Secale cereale L

Lunasin

Dia et al., 2011

Non specific

Rabdosia rubescens

Oridonin

Gao et al., 2010

Non specific

vegetables and fruits

Phytosterols

Choudhary & Tran, 2011

Non specific

 

Plumbagin

Chen et al., 2013

Non specific

Panax ginseng

RG3

Wang et al., 2006

Non specific

 

Rosmarinic acid

Ngo et al., 2011

Non specific

Bupleurum radix

Saikosaponin-A

Kim & Hong, 2011

Non specific

Salvia miltiorrhiza

Tanshinone II A

Tu et al., 2012

Non specific

Stephania tetrandra

Tetrandrine

Lai et al., 1998;

Ng et al., 2006;

Wu et al., 2010;

He et al., 2011

Non specific

Camellia sinensis

Theaflavin-2

Gosslau et al., 2011

Non specific

Nigella sativa

Thymoquinone

Roepke et al., 2007

Non specific

Rosmarinus officinalis,

Salvia officinalis,

Prunella vulgaris,

Psychotria serpens

Hyptis capitata

Ursolic acid

Ngo et al., 2011

 

Rectal Cancer

Cell Type

Herb Source(s)

Isolate

Refs

Non specific

Sophora Flavescens

Matrine

Yin et al., 2013
AhR, Akt, angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, anxiolytic, apoptosis, Apoptotic, BAX, Bcl-2, Breast cancer, CAL-27, FaDu, cardio-protective, cardio-protective against Doxorubicin, cardiovascular disease, Causes cell-cycle arrest, CDK4, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, Cytostatic, cytotoxic, G1, G2/M, Head and neck cancer, Hep G2,Hep 3B and SK-Hep1, HIF, HL-60/ADR, IL-6, inflammation, iNOS, JNK, MCF-7, T-47D, MDA-MB-231, Nitric Oxide, Oral cancer, Ovarian cancer, Ovarian cancer cell lines, OVCAR-3, CP-70, IOSE-364, p53, Prostate cancer, ROS, S, VEGF, VEGF, XIAP

Baicalin & Baicalein

Cancer:
Myeloma, liver, colorectal., breast, prostate, oral., hepatoma, ovarian

Action: Anti-cancer, cardiovascular disease, cytostatic, cardio-protective against Doxorubicin, anti-inflammatory, angiogenesis

Baicalin and baicalein are naturally occurring flavonoids that are found in the roots and leaves of some Chinese medicinal plants (including Scutellaria radix, Scutellaria rivularis (Benth.); Scutellaria baicalensis (Georgi) and Scutellaria lateriflora (L.)) are thought to have anti-oxidant activity and possible anti-angiogenic, anti-cancer, anxiolytic, anti-inflammatory and neuroprotective activities. In particular, Scutellaria baicalensis is one of the most popular and multi-purpose herbs used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, and bacterial and viral infections (Ye et al., 2002; Zhang et al., 2011a).

Anti-cancer

Accumulating evidence demonstrates that Scutellaria also possesses potent anti-cancer activities. The bioactive components of Scutellaria have been confirmed to be flavones, wogonin, baicalein and baicalin. These phytochemicals are not only cytostatic but also cytotoxic to various human tumor cell lines in vitro and inhibit tumor growth in vivo. Most importantly, they show almost no or minor toxicity to normal epithelial and normal peripheral blood and myeloid cells. The anti-tumor functions of these flavones are largely due to their abilities to scavenge oxidative radicals, to attenuate NF-kappaB activity, to inhibit several genes important for regulation of the cell-cycle, to suppress COX-2 gene expression and to prevent viral infections (Li, 2008).

Multiple Myeloma

In the search for a more effective adjuvant therapy to treat multiple myeloma (MM), Ma et al. (2005) investigated the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du-Tang (HLJDT), Gui-Zhi-Fu-Ling-Wan (GZFLW), and Huang-Lian-Tang (HLT) on the proliferation and apoptosis of myeloma cells. HLJDT inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially MPC-1- immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3.

Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect of HLJDT on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin. Baicalein as well as baicalin suppressed the survival in vitro of MPC-1- immature myeloma cells rather than MPC-1+ myeloma cells from myeloma patients.

Baicalein inhibited the phosphorylation of IkB-alpha, which was followed by decreased expression of the IL-6 and XIAP genes and activation of caspase-9 and caspase-3. Therefore, HLJDT and Scutellaria radix have an anti-proliferative effect on myeloma cells, especially MPC-1- immature myeloma cells, and baicalein may be responsible for the suppressive effect of Scutellaria radix by blocking IkB-alpha degradation (Ma, 2005).

Hepatoma

The effects of the flavonoids from Scutellaria baicalensis Georgi (baicalein, baicalin and wogonin) in cultured human hepatoma cells (Hep G2, Hep 3B and SK-Hep1) were compared by MTT assay and flow cytometry. All three flavonoids dose-dependently decreased the cell viabilities accompanying the collapse of mitochondrial membrane potential and the depletion of glutathione content. However, the influence of baicalein, baicalin or wogonin on cell-cycle progression was different.

All three flavonoids resulted in prominent increase of G2/M population in Hep G2 cells, whereas an accumulation of sub G1 (hypoploid) peak in Hep 3B cells was observed. In SK-Hep1 cells, baicalein and baicalin resulted in a dramatic boost in hypoploid peak, but wogonin mainly in G1 phase accumulation. These data, together with the previous findings in other hepatoma cell lines, suggest that baicalein, baicalin and wogonin might be effective candidates for inducing apoptosis or inhibiting proliferation in various human hepatoma cell lines (Chang, 2002).

Long dan xie gan tang (pinyin) is one of the most commonly used herbal formulas by patients with chronic liver disease in China. Accumulated anecdotal evidence suggests that Long dan tang may have beneficial effects in patients with hepatocellular carcinoma. Long dan tang is comprised of five herbs: Gentiana root, Scutellaria root, Gardenia fruit, Alisma rhizome, and Bupleurum root. The cytotoxic effects of compounds from the five major ingredients isolated from the above plants, i.e. gentiopicroside, baicalein, geniposide, alisol B acetate and saikosaponin-d, were investigated, respectively, on human hepatoma Hep3B cells..

Interestingly, baicalein by itself induced an increase in H(2)O(2) generation and the subsequent NF-kappaB activation; furthermore, it effectively inhibited the transforming growth factor-beta(1) (TGF-beta(1))-induced caspase-3 activation and cell apoptosis. Results suggest that alisol B acetate and saikosaponin-d induced cell apoptosis through the caspase-3-dependent and -independent pathways, respectively. Instead of inducing apoptosis, baicalein inhibits TGF-beta(1)-induced apoptosis via increase in cellular H(2)O(2) formation and NF-kappaB activation in human hepatoma Hep3B cells (Chou, Pan, Teng & Guh, 2003).

Ovarian Cancer

Ovarian cancer is one of the primary causes of death for women all through the Western world. Two kinds of ovarian cancer (OVCAR-3 and CP-70) cell lines and a normal ovarian cell line (IOSE-364) were selected to be investigated in the inhibitory effect of baicalin and baicalein on cancer cells. Largely, baicalin and baicalein inhibited ovarian cancer cell viability in both ovarian cancer cell lines with LD50 values in the range of 45-55 µM for baicalin and 25-40 µM for baicalein. On the other hand, both compounds had fewer inhibitory effects on normal ovarian cells viability with LD50 values of 177 µM for baicalin and 68 µM for baicalein.

Baicalin decreased expression of VEGF (20 µM), cMyc (80 µM), and NFkB (20 µM); baicalein decreased expression of VEGF (10 µM), HIF-1α (20 µM), cMyc (20 µM), and NFkB (40 µM). Therefore baicalein is more effective in inhibiting cancer cell viability and expression of VEGF, HIF-1α, cMyc, and NFκB in both ovarian cancer cell lines. It seems that baicalein inhibited cancer cell viability through the inhibition of cancer promoting genes expression including VEGF, HIF-1α, cMyc, and NFκB.

Overall, this study showed that baicalein and baicalin significantly inhibited the viability of ovarian cancer cells, while generally exerting less of an effect on normal cells. They have potential for chemoprevention and treatment of ovarian cancers (Chen, 2013).

Breast Cancer

Baicalin was found to be a potent inhibitor of mammary cell line MCF-7 and ductal breast epithelial tumor cell line T-47D proliferation, as well as having anti-proliferative effects on other cancer types such as the human head and neck cancer epithelial cell lines CAL-27 and FaDu. Overall, baicalin inhibited the proliferation of human breast cancer cells and CAL-27 and FaDu cells with effective potency (Franek, 2005).

Breast Cancer, Cell Invasion

The effect of Baicalein on cell viability of the human breast cancer MDA-MB-231 cell line was tested by MTT. 50, 100 µmol·L-1 of Baicalein inhibited significantly cell invasion(P0.01) and migration(P0.01) compared with control groups. The inhibitory rates were 50% and 77% in cell migration and 15% and 44% in cell invasion, respectively. 50 µmol·L-1 of Baicalein significantly inhibited the level of MMP 2 expression. 100 µmol·L-1 of Baicalein significantly inhibited the level of MMP 9 and uPA expressions.

Baicalein inhibits invasion and migration of MDA-MB-231 cells. The mechanisms may be involved in the direct inhibition of cell invasion and migration abilities, and the inhibition of MMP 2, MMP 9, and uPA expressions (Wang et al., 2010).

The proliferation of MDA-MB-231 cell line human breast adenocarcinoma was inhibited by baicalin in a dose-and time-dependent manner and the IC50 was 151 µmol/L. The apoptotic rate of the baicalin-treated MDA-MB-231 cells increased significantly at 48 hours. Flow cytometer analysis also revealed that most of the baicalin-treated MDA-MB-231 cells were arrested in the G2/M phase. Typically apoptotic characteristics such as condensed chromatin and apoptotic bodies were observed after being treated with baicalin for 48 hours.

The results of RT-PCR showed that the expression of bax was up-regulated; meanwhile, the expression of bcl-2 was down-regulated. Baicalin could inhibit the proliferation of MDA-MB-231 cells through apoptosis by regulating the expression of bcl-2, bax and intervening in the process of the cell-cycle (Zhu et al., 2008).

Oral Cancer

As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell-cycle, it is suspected that the anti-cancer effect of baicalein is associated with AhR. The molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3 has been investigated, including whether such an effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell-cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased.

When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is mediated by baicalein both through activation of AhR and facilitation of cyclin D1 degradation, which causes cell-cycle arrest at the G1 phase, and results in the inhibition of cell proliferation (Cheng, 2012).

Anti-inflammatory

Baicalin has also been examined for its effects on LPS-induced nitric oxide (NO) production and iNOS and COX-2 gene expressions in RAW 264.7 macrophages. The results indicated that baicalin inhibited LPS-induced NO production in a concentration-dependent manner without a notable cytotoxic effect on these cells. The decrease in NO production was consistent with the inhibition by baicalin of LPS-induced iNOS gene expression (Chen, 2001)

Angiogenesis Modulation

The modulation of angiogenesis is one possible mechanism by which baicalin may act in the treatment of cardiovascular diseases. This may be elucidated by investigating the effects of baicalin on the expression of vascular endothelial growth factor (VEGF), a critical factor for angiogenesis. The effects of baicalin and an extract of S. baicalensis on VEGF expression were tested in several cell lines. Both agents induced VEGF expression in all cells without increasing expression of hypoxia-inducible factor-1alpha (HIF-1alpha).

Their ability to induce VEGF expression was suppressed once ERRalpha expression was knocked down by siRNA, or ERRalpha-binding sites were deleted in the VEGF promoter. It was also found that both agents stimulated cell migration and vessel sprout formation from the aorta. These results therefore implicate baicalin and S. baicalensis in angiogenesis by inducing VEGF expression through the activation of the ERRalpha pathway (Zhang, 2011b).

Colon Cancer

The compounds of baicalein and wogonin, derived from the Chinese herb Scutellaria baicalensis, were studied for their effect in suppressing the viability of HT-29 human colon cancer cells. Following treatment with baicalein or wogonin, several apoptotic events were observed, including DNA fragmentation, chromatin condensation and increased cell-cycle arrest at the G1 phase. Baicalein and wogonin decreased Bcl-2 expression, whereas the expression of Bax was increased in a dose-dependent manner when compared to the control.

The results indicated that baicalein induced apoptosis via Akt activation, in a p53-dependent manner, in HT-29 colon cancer cells. Baicalein may serve as a chemo-preventive, or therapeutic, agent for HT-29 colon cancer (Kim et al., 2012).

Cardio-protective

The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of malignancies. Previous studies suggest that doxorubicin-associated cardiotoxicity is mediated by reactive oxygen species (ROS)-induced apoptosis. Baicalein attenuated phosphorylation of JNK induced by doxorubicin. Co-treatment of cardiomyocytes with doxorubicin and JNK inhibitor SP600125 (10 µM; 24 hours) reduced JNK phosphorylation and enhanced cell survival., suggesting that the baicalein protection against doxorubicin cardiotoxicity was mediated by JNK activation. Baicalein adjunct treatment confers anti-apoptotic protection against doxorubicin-induced cardiotoxicity without compromising its anti-cancer efficacy (Chang et al., 2011).

Prostate Cancer

There are four compounds capable of inhibiting prostate cancer cell proliferation in Scutellaria baicalensis: baicalein, wogonin, neobaicalein, and skullcapflavone. Comparisons of the cellular effects induced by the entire extract versus the four-compound combination produced comparable cell-cycle changes, levels of growth inhibition, and global gene expression profiles (r(2) = 0.79). Individual compounds exhibited anti-androgenic activities with reduced expression of the androgen receptor and androgen-regulated genes. In vivo, baicalein (20 mg/kg/d p.o.) reduced the growth of prostate cancer xenografts in nude mice by 55% at 2 weeks compared with placebo and delayed the average time for tumors to achieve a volume of approximately 1,000 mm(3) from 16 to 47 days (P < 0.001).

Most of the anti-cancer activities of S. baicalensis can be recapitulated with four purified constituents that function in part through inhibition of the androgen receptor signaling pathway (Bonham et al., 2005)

Cancer: Acute lymphocytic leukemia, lymphoma and myeloma

Action: Cell-cycle arrest, induces apoptosis

Scutellaria baicalensis (S.B.) is a widely used Chinese herbal medicine. S.B inhibited the growth of acute lymphocytic leukemia (ALL), lymphoma and myeloma cell lines by inducing apoptosis and cell cycle arrest at clinically achievable concentrations. The anti-proliferative effectwas associated with mitochondrial damage, modulation of the Bcl family of genes, increased level of the CDK inhibitor p27KIP1 and decreased level of c-myc oncogene. HPLC analysis of S.B. showed it contains 21% baicalin and further studies confirmed it was the major anti-cancer component of S.B. Thus, Scutellaria baicalensis should be tested in clinical trials for these hematopoietic malignancies (Kumagai et al., 2007).

References

Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson PS. (2005). Characterization of chemical constituents in Scutellaria baicalensis with antiandrogenic and growth-inhibitory activities toward prostate carcinoma. Clin Cancer Res, 11(10):3905-14.


Chang WH Chen CH Lu FJ. (2002). Different Effects of Baicalein, Baicalin and Wogonin on Mitochondrial Function, Glutathione Content and cell-cycle Progression in Human Hepatoma Cell Lines. Planta Med, 68(2):128-32. doi: 10.1055/s-2002-20246


Chang WT, Li J, Huang HH, et al. (2011). Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury .and JNK activation. J Cell Biochem. doi: 10.1002/jcb.23201.


Chen J, Li Z, Chen AY, Ye X, et al. (2013). Inhibitory effect of baicalin and baicalein on ovarian cancer cells. Int J Mol Sci, 14(3):6012-25. doi: 10.3390/ijms14036012.


Chen YC, Shen SC, Chen LG, Lee TJ, Yang LL. (2001). Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide. Biochem Pharmacol,61(11):1417-27. doi:10.1016/S0006-2952(01)00594-9


Cheng YH, Li LA, Lin P, et al. (2012). Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation. Toxicol Appl Pharmacol, 263(3):360-7. doi: 10.1016/j.taap.2012.07.010.


Chou CC, Pan SL, Teng CM, & Guh JH. (2003). Pharmacological evaluation of several major ingredients of Chinese herbal medicines in human hepatoma Hep3B cells. European Journal of Pharmaceutical Sciences, 19(5), 403-12.


Franek KJ, Zhou Z, Zhang WD, Chen WY. (2005). In vitro studies of baicalin alone or in combination with Salvia miltiorrhiza extract as a potential anti-cancer agent. Int J Oncol, 26(1):217-24.


Kim SJ, Kim HJ, Kim HR, et al. (2012). Anti-tumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Molecular Medicine Reports, 6(6):1443-1449. doi: 10.3892/mmr.2012.1085.


Li-Weber M. (2009). New therapeutic aspects of flavones: The anti-cancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev, 35(1):57-68. doi: 10.1016/j.ctrv.2008.09.005.


Ma Z, Otsuyama K, Liu S, et al. (2005). Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells. Blood, 105(8):3312-8. doi:10.1182/blood-2004-10-3915.


Wang Xf, Zhou Qm, Su Sb. (2010). Experimental study on Baicalein inhibiting the invasion and migration of human breast cancer cells. Zhong Guo Yao Li Xue Tong Bao, 26(6): 745-750.


Zhang XW, Li WF, Li WW, et al. (2011a). Protective effects of the aqueous extract of Scutellaria baicalensis against acrolein-induced oxidative stress in cultured human umbilical vein endothelial cells. Pharm Biol, 49(3): 256–261. doi:10.3109/13880209.2010.501803.


Ye F, Xui L, Yi J, Zhang, W, Zhang DY. (2002). Anti-cancer activity of Scutellaria baicalensis and its potential mechanism. J Altern Complement Med, 8(5):567-72.


Zhang K, Lu J, Mori T, et al. (2011b). Baicalin increases VEGF expression and angiogenesis by activating the ERR{alpha}/PGC-1{alpha} pathway.[J]. Cardiovascular Research, 89(2):426-435.


Zhu Gq, Tang Lj, Wang L, Su Jj, et al. (2008). Study on Baicalin Induced Apoptosis of Human Breast Cancer Cell Line MDA-MB-231. An Hui Zhong Yi Xue Yuan Xue Bao, 27(2):20-23

Kumagai T, et al. (2007) Scutellaria baicalensis, a herbal medicine: Anti-proliferative and apoptotic activity against acute lymphocytic leukemia, lymphoma and myeloma cell lines. Leukemia Research 31 (2007) 523-530

Akt, anti-apoptotic, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, epidermal growth factor receptor, G2/M, growth-inhibitory, HepG2, HER-2, HER-2/neu, HER2, HIF, HL-60, HL-60/ADR, induces apoptosis, Induces cytotoxicity, inflammation, JAK2, LS1034, Lung cancer, Mahlavu, PLC/PRF/5 and HepG2, Mcl-1, MDA-MB-231, MDR, MDR-1, MDR-1, MTOR, P-gp, p21, p53, Pancreatic cancer, ROS, S, STAT3

Emodin (See also Aloe-Emodin)

Cancer:
Breast, colon, liver, chemotherapy, myeloma, oral., pancreatic, hepatocellular carcinoma, lung, leukemia

Action: MDR-1, cell-cycle arrest

Emodin is an active natural anthraquinone derivative component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L., Senna obtusifolia [(L.) H.S.Irwin & Barneby], Fallopia japonica [Houtt. (Ronse Decr.)], Kalimeris indica (L.) Sch.Bip., Ventilago madraspatana (Gaertn.), Rumex nepalensis (Spreng.), Fallopia multiflora [(Thunb.) Haraldson], Cassia occidentalis [(L.) Link], Senna siamea [(Lam.) Irwin et Barneby] and Acalypha australis (L.).

Aloe-emodin is an active natural anthraquinone derivative, and is found in the roots and rhizomes of numerous Chinese medicinal herbs (including Rheum palmatum L) and exhibits anti-cancer effects on many types of human cancer cell lines.

Administration of rhubarb (Emodin) can effectively reverse severe acute pancreatitis (SAP) by regulating the levels of IL-15 and IL-18 (Yu & Yang, 2013).

Pancreatic Cancer

Emodin is a tyrosine kinase inhibitor that has an inhibitory effect on mammalian cell-cycle modulation in specific oncogene-overexpressing cells. Recently, there has been great progress in the preclinical study of the anti-cancer mechanisms of emodin. A recent study revealed that emodin has therapeutic effects on pancreatic cancer through various anti-tumor mechanisms. Notably, the therapeutic efficacy of emodin in combination with chemotherapy was found to be higher than the comparable single chemotherapeutic regime, and the combination therapy also exhibited fewer side-effects (Wei et al., 2013).

Hepatocellular Carcinoma, Pancreatic, Breast, Colorectal and Lung Cancers, and Leukemia

Emodin is found as an active ingredient in different Chinese herbs including Rheum palmatum and Polygonam multiflorum, and has diuretic, vasorelaxant, anti-bacterial., anti-viral., anti-ulcerogenic, anti-inflammatory, and anti-cancer effects. The anti-inflammatory effects of emodin have been exhibited in various in vitro as well as in vivo models of inflammation including pancreatitis, arthritis, asthma, atherosclerosis and glomerulonephritis. As an anti-cancer agent, emodin has been shown to suppress the growth of various tumor cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal., leukemia, and lung cancers. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-κB, casein kinase II, HER2/neu, HIF-1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer (Shrimali et al., 2013).

Hepatocellular Carcinoma

It has been found that emodin induces apoptotic responses in the human hepatocellular carcinoma cell lines (HCC) Mahlavu, PLC/PRF/5 and HepG2. The addition of emodin to these three cell lines led to inhibition of growth in a time-and dose-dependent manner. Emodin generated reactive oxygen species (ROS) in these cells which brought about a reduction of the intracellular mitochondrial transmembrane potential (ΔΨ m), followed by the activation of caspase–9 and caspase–3, leading to DNA fragmentation and apoptosis.

Preincubation of hepatoma cell lines with the hydrogen peroxide-scavenging enzyme, catalase (CAT) and cyclosporin A (CsA), partially inhibited apoptosis. These results demonstrate that enhancement of generation of ROS, DeltaPsim disruption and caspase activation may be involved in the apoptotic pathway induced by emodin (Jing et al., 2002).

Colon Cancer

In in vitro study, emodin induced cell morphological changes, decreased the percentage of viability, induced G2/M phase arrest and increased ROS and Ca(2+) productions as well as loss of mitochondrial membrane potential (ΔΨ(m)) in LS1034 cells. Emodin-triggered apoptosis was also confirmed by DAPI staining and these effects are concentration-dependent.

In in vivo study, emodin effectively suppressed tumor growth in tumor nude mice xenografts bearing LS1034. Overall, the potent in vitro and in vivo anti-tumor activities of emodin suggest that it might be developed for treatment of colon cancer in the future (Ma et al., 2012).

Myeloid Leukemia

It has been shown that emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukemia 1 (Mcl-1). Emodin inhibited interleukin-6–induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other anti-apoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. To clarify the importance of Mcl-1 in emodin-induced apoptosis, the Mcl-1 expression vector was introduced into the human myeloma cells by electroporation. Induction of apoptosis by emodin was almost abrogated in Mcl-1–overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. Emodin therefore inhibits interleukin-6–induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, these results show emodin as a new potent anti-cancer agent for the treatment of multiple myeloma patients (Muto et al., 2007).

Breast Cancer; Block HER-2

The mechanism by which emodin prevents breast cancer is unknown; however the product of the HER-2/neu proto-oncogene, HER2 has been proposed to be involved. The product of the HER-2/neu proto-oncogene, HER2, is the second member of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors and has been suggested to be a ligand orphan receptor. Amplification of the HER2 gene and overexpression of the HER2 protein induces cell transformation and has been demonstrated in 10% to 40% of human breast cancer. HER2 overexpression has been suggested to associate with tumor aggressiveness, prognosis and responsiveness to hormonal and cytotoxic agents in breast cancer patients. These findings indicate that HER2 is an appropriate target for tumor-specific therapies.

A number of approaches have been investigated: (1) a humanized monoclonal antibody against HER2, rhuMAbHER2 (trastuzumab), which is already approved for clinical use in the treatment of patients with metastatic breast cancer; (2) tyrosine kinase inhibitors, such as emodin, which block HER2 phosphorylation and its intracellullar signaling; (3) active immunotherapy, such as vaccination; and (4) heat shock protein (Hsp) 90-associated signal inhibitors, such as radicicol derivatives, which induce degradation of tyrosine kinase receptors, such as HER2 (Kurebayashi, 2001).

MDR

The effects of emodin on the nucleoside transport and multi-drug resistance in cancer cells has also been investigated. Nucleoside transport inhibition was determined by thymidine incorporation assay. The cytotoxicity to cancer cells was determined by MTT assay. The pump efflux activity and the expression of P glycoprotein were examined by flow cytometric assay. Emodin was active in the inhibition of nucleoside transport, with an IC 50 value of 9 9 µmol·L -1. Emodin markedly enhanced the cytotoxicity of 5 FU, MMC and MTX against human hepatoma BEL 7402 cells and partly reversed the multi-drug resistance in human breast cancer MCF 7/Adr cells.

Emodin inhibited P-gp pump efflux activity and reduced the expression of P gp in MCF 7/Adr cells. These findings provide a biological basis for the application of emodin as a biochemical modulator to potentiate the effects of anti-tumor drugs and reverse the multi-drug resistance in cancer cells (Jiang et al., 2009).

Cell-cycle Arrest

Large quantities of emodin were isolated from the roots of Rheum emodi and a library of novel emodin derivatives 2–15 were prepared to evaluate their anti-proliferative activities against HepG2, MDA-MB-231 and NIH/3T3 cells lines. The derivatives 3 and 12 strongly inhibited the proliferation of HepG2 and MDA-MB-231 cancer cell line with an IC50 of 5.6, 13.03 and 10.44, 5.027, respectively, which is comparable to marketed drug epirubicin (III). The compounds 3 and 12 were also capable of inducing cell-cycle arrest and caspase dependent apoptosis in HepG2 cell lines and exhibit DNA intercalating activity. These emodin derivatives hold promise for developing safer alternatives to the marketed epirubicin (Narender et al., 2013).

Cell-cycle Arrest; MDR1 & AZT

3'-azido-3'-deoxythymidine (AZT) and emodin altered the cell-cycle distribution and led to an accumulation of cells in S phase. Meanwhile, the expression of MDR1 mRNA/p-gp protein was markedly decreased. These results show a synergistic growth-inhibitory effect of AZT and emodin in K562/ADM cells, which is achieved through S phase arrest. MDR1 might ultimately be responsible for these phenomena (Chen et al., 2013).

References

Chen P, Liu Y, Sun Y, et al. (2013). AZT and emodin exhibit synergistic growth-inhibitory effects on K562/ADM cells by inducing S phase cell-cycle arrest and suppressing MDR1 mRNA/p-gp protein expression. Pharm Biol.


Garg AK, Buchholz TA, Aggarwal BB. (2005). Chemo-sensitization and Radiosensitization of Tumors by Plant Polyphenols. Antioxid Redox Signal., 7(11-12):1630-47.


Jiang XF & Zhen YS. (1999). Reversal of Multi-drug resistance by emodin in cancer cells. Acta Pharmaceutica Sinica, 1999-03.


Jing X, Ueki N, Cheng J, Imanishi H, Hada T. (2002). Induction of apoptosis in hepatocellular carcinoma cell lines by emodin. Cancer Science, 93(8):874–882.


Kurebayashi J. (2001). Biological and clinical significance of HER2 overexpression in breast cancer. Breast Cancer, 8(1):45-51


Ma YS, Weng SW, Lin MW, et al. (2012). Anti-tumor effects of emodin on LS1034 human colon cancer cells in vitro and in vivo: Roles of apoptotic cell death and LS1034 tumor xenografts model. Food Chem Toxicol, 50(5): 1271–1278. doi: 10.1016/j.fct.2012.01.033.


Muto A, Hori M, Sasaki Y, et al. (2007). Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor. Mol Cancer Ther. doi: 10.1158/1535-7163.MCT-06-0605.


Narender T, Sukanya P, Sharma K, et al. (2013). Preparation of novel anti-proliferative emodin derivatives and studies on their cell-cycle arrest, caspase dependent apoptosis and DNA binding interaction. Phytomedicine, 20(10):890-896.


Shrimali D, Shanmugam MK, Kumar AP, et al. (2013). Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer. Cancer Lett:S0304-3835(13)00598-3. doi: 10.1016/j.canlet.2013.08.023.


Wei WT, Lin SZ, Liu DL, Wang ZH. (2013). The distinct mechanisms of the anti-tumor activity of emodin in different types of cancer (Review). Oncol Rep. doi: 10.3892/or.2013.2741.


Yu XW, Yang RZ. (2013). Effects of crude rhubarb on serum IL-15 and IL-18 levels in patients with severe acute pancreatitis. An Hui Yi Xue, 34(3): 285-287.

A549, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, Antibiotic, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, Chemo-protective, Colon Cancer or Colorectal cancer, CSK, Dox-induced cardiotoxicity, Doxorubicin-induced cardotoxicity, Eca-109, Esophageal cancer, Hippophae rhamnoides, HL-60, HT-29, K562, Lung cancer, Lymphoma, Rectal cancer, YAC-1

Isorhamnetin

Cancer:
Lung, colon, acute myeloid leukemia, T lymphoma, Ehrlich carcinoma, gastric, esophageal squamous cell, chronic myelogenous leukemia

Action: Dox-induced cardiotoxicity, anti-oxidant

Isorhamnetin, the anti-tumor component of Hippophae rhamnoides Linn, is also a member of the ßavonoid class of compounds. Its chemical name is 3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl) chromen-4-one and its molecular formula is C16H12O7.

Lung Cancer

Isorhamnetin shows good inhibitory effects on human lung adenocarcinoma A549 cells, human colon cancer HT-29 cells, human chronic myeloid leukemia K562 cells, human acute myeloid leukemia HL-60 cells, mouse T lymphoma YAC-1 cells and mouse Ehrlich carcinoma. In terms of its mechanism of action, it seems that isorhamnetin simultaneously reduces the expression of Bcl-2 and increases the expression of Bax, which activates caspase-9 and its downstream factor caspase-3, thus resulting in cell death (Zhu et al. 2005).

Colorectal Cancer

It was demonstrated that isorhamnetin prevents colorectal tumorigenesis. Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. Magnetic resonance imaging, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than control diet.

These observations suggest the chemo-protective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression (Saud et al., 2013).

Gastric Cancer

The potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, were investigated on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, gastric cancer (GC) cell lines, and xenograft mice model.

It was observed that IH exerted a strong anti-proliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of gastric cancer cells, which could be reversed in the presence of PPAR-γ inhibitor.

Using molecular docking analysis, Ramachandran et al. (2013) demonstratd that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, these findings clearly indicate that anti-tumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.

Cardiac-protective; Doxorubicin

Isorhamnetin is a natural anti-oxidant with obvious cardiac-protective effect. Its action against doxorubicin-induced cardotoxicity and underlying mechanisms were investigated. Doxorubicin (Dox) is an anthracycline antibiotic for cancer therapy with limited usage due to cardiotoxicity. The aim of this study is to investigate the possible protective effect of isorhamnetin against Dox-induced cardiotoxicity and its underlying mechanisms. In an in vivo investigation, rats were intraperitoneally (i.p.) administered with Dox to duplicate the model of Dox-induced chronic cardiotoxicity.

Daily pre-treatment with isorhamnetin (5 mg/kg, i.p.) for 7 days was found to reduce Dox-induced myocardial damage significantly, including the decline of cardiac index, decrease in the release of serum cardiac enzymes, and amelioration of heart vacuolation. In vitro studies on H9c2 cardiomyocytes, isorhamnetin was effective to reduce Dox-induced cell toxicity. Isorhamnetin also potentiated the anti-cancer activity of Dox in MCF-7, HepG2 and Hep2 cells. These findings indicated that isorhamnetin can be used as an adjuvant therapy for the long-term clinical use of Dox (Sun et al., 2013).

Chronic Myelogenous Leukemia

The isorhamnetin 3-o-robinobioside and its original extract, ethyl acetate extract, from Nitraria retusa leaves, were evaluated for their ability to induce anti-oxidant and anti-genotoxic effects in human chronic myelogenous leukemia cell line. They were shown to have a great anti-oxidant and anti-genotoxic potential on human chronic myelogenous leukemia cell line K562 (Boubaker et al., 2012).

Esophageal Cancer

The flavonol aglycone isorhamnetin shows anti-proliferative activity in a variety of cancer cells and it inhibits the proliferation of human esophageal squamous carcinoma Eca-109 cells in vitro (Shi et al., 2012).

Cancer:
Actions: Overcomes MDR; P-glycoproteins, breast cancer resistance proteins (BCRP), efflux transporters

Flavonoid isorhamnetin occurs in various plants and herbs, and demonstrates various biological effects in humans. This work will clarify the isorhamnetin absorption mechanism using the Caco-2 monolayer cell model. The isorhamnetin transport characteristics at different concentrations, pHs, temperatures, tight junctions and potential transporters were systemically investigated.

Isorhamnetin was poorly absorbed by both passive diffusion and active transport mechanisms. Both trans- and paracellular pathways were involved during isorhamnetin transport. Active transport under an ATP-dependent transport mechanism was mediated by the organic anion transporting peptide (OATP); isorhamnetin’s permeability from the apical to the basolateral side significantly decreased after estrone-3-sulfate was added (p<0.01).

Efflux transporters, P-glycoproteins (P-gp), breast cancer resistance proteins (BCRP) and multidrug resistance proteins (MRPs) participated in the isorhamnetin transport process. Among them, the MRPs (especially MRP2) were the main efflux transporters for isorhamnetin; transport from the apical to the basolateral side increased 10.8-fold after adding an MRP inhibitor (MK571).

References

Boubaker J, Ben Sghaier M, Skandrani I, et al. (2012). Isorhamnetin 3-O-robinobioside from Nitraria retusa leaves enhance anti-oxidant and anti-genotoxic activity in human chronic myelogenous leukemia cell line K562. BMC Complement Altern Med, 12:135. doi: 10.1186/1472-6882-12-135.


Ramachandran L, Manu KA, Shanmugam MK, et al. (2013). Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer. J Biol Chem, 288(26):18777. doi: 10.1074/jbc.A112.388702.


Saud SM, Young MR, Jones-Hall YL, et al. (2013). Chemo-preventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β -catenin. Cancer Res, 73:5473.


Shi C, Fan LY, Cai Z, Liu YY, Yang CL. (2012). Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin. Neoplasma, 59(4):361-9. doi: 10.4149/neo_2012_047.


Sun J, Sun G, Meng X, et al. (2013). Isorhamnetin protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. PLoS One, 8(5):e64526. doi: 10.1371/journal.pone.0064526.


Zhu L, Wang ZR, Zhou LM, et al. (2005). Effects and mechanisms of isorhamnetin on lung carcinoma. Space Med Med Eng (Chin), 18:381-383.


Duan J, Xie Y, Luo H, Li G, Wu T, Zhang T. (2014) Transport characteristics of isorhamnetin across intestinal Caco-2 cell monolayers and the effects of transporters on it. Food Chem Toxicol. 2014 Apr;66:313-20. doi: 10.1016/j.fct.2014.02.003.

AMPK, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-proliferative, anti-proliferative effect, anti-tumor, apoptosis, apoptosis-inducing, Apoptotic, autophagic cell death, Autophagy, BAD, BAX, Bcl-2, Breast cancer, Breast cancer cell lines, c-Myc, cancer stem cells, cardio-protective, CCAAT, CDK, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, CNE, Colon Cancer or Colorectal cancer, COX-2, CSC, CSCs, Cytostatic, cytotoxic, ER, ERK, G0/G1, G1, GADD153, growth-inhibitory, HepG2, SMMC-7721, ICAM-1, IL-6, inflammation, K562, KBM-5, LNCaP, MTOR, p16, p21, p27, PC3 and LNCaP, Pro-apoptotic, Prostate cancer, Rectal cancer, RSK, S, SGC7901, STAT3, T47D, MDA-MB-231, TNF, U937, MDA-MB-231, VCAM-1, VEGF, VEGF

Tanshinone II A & Tanshinone A (See also Cryptotanshinone)

Cancer:
Leukemia, prostate, breast, gastric, colorectal, nasopharyngeal carcinoma

Action: Chemo-sensitizer, cytostatic, cancer stem cells, anti-cancer, autophagic cell death, cell-cycle arrest

Anti-cancer

Tanshinone IIA and cryptotanshinone could induce CYP3A4 activity (Qiu et al., 2103).

Tanshinone II-A (Tan IIA) is the most abundant diterpene quinone isolated from Danshen (Salvia miltiorrhiza), which has been used in treating cardiovascular diseases for more than 2,000 years in China. Interest in its versatile protective effects in cardiovascular, metabolic, neurodegenerative diseases, and cancers has been growing over the last decade.

Tan IIA is a multi-target drug, whose molecular targets include transcription factors, scavenger receptors, ion channels, kinases, pro- and anti-apoptotic proteins, growth factors, inflammatory mediators, microRNA, and others. More recently, enhanced or synergistic effects can be observed when Tan IIA is used in combination therapy with cardio-protective and anti-cancer drugs (Xu & Liu, 2013).

Leukemia

The in vitro anti-proliferation and apoptosis-inducing effects of Tanshinone IIA on leukemia THP-1 cell lines and its mechanisms of action were investigated. MTT assay was used to detect the cell growth-inhibitory rate; cell apoptotic rate and the mitochondrial membrane potential (Deltapsim) were investigated by flow cytometry (FCM); apoptotic morphology was observed by Hoechst 33258 staining and DNA fragmentation analysis.

It was therefore concluded that Tanshinone IIA has significant growth inhibition effects on THP-1 cells by induction of apoptosis, and that Tanshinone IIA-induced apoptosis on THP-1 cells is mainly related to the disruption of Deltapsim and activation of caspase-3 as well as down-regulation of anti-apoptotic protein Bcl-2, survivin and up-regulation of pro-apoptotic protein Bax. The results indicate that Tanshinone IIA may serve as a potential anti-leukemia agent (Liu et al., 2009).

Prostate Cancer

Chiu et al. (2013) explored the mechanisms of cell death induced by Tan-IIA treatment in prostate cancer cells in vitro and in vivo. Results showed that Tan-IIA caused prostate cancer cell death in a dose-dependent manner, and cell-cycle arrest at G0/G1 phase was noted, in LNCaP cells. The G0/G1 phase arrest correlated with increased levels of CDK inhibitors (p16, p21 and p27) and decrease of the checkpoint proteins. Tan-IIA also induced ER stress in prostate cancer cells: activation and nuclear translocation of GADD153/CCAAT/enhancer-binding protein-homologous protein (CHOP) were identified, and increased expression of the downstream molecules GRP78/BiP, inositol-requiring protein-1α and GADD153/CHOP were evidenced. Blockage of GADD153/CHOP expression by siRNA reduced Tan-IIA-induced cell death in LNCaP cells.

Gastric Cancer

Tan IIA can reverse the malignant phenotype of SGC7901 gastric cancer cells, indicating that it may be a promising therapeutic agent.

Tan IIA (1, 5, 10 µg/ml) exerted powerful inhibitory effects on cell proliferation (P < 0.05, and P < 0.01), and this effect was time- and dose-dependent. FCM results showed that Tan IIA induced apoptosis of SGC7901 cells, reduced the number of cells in S phase and increased those in G0/G1 phase. Tan IIA also significantly increased the sensitivity of SGC7901 gastric cancer cells to ADR and Fu. Moreover, wound-healing and transwell assays showed that Tan IIA markedly decreased migratory and invasive abilities of SGC7901 cells (Xu et al., 2013).

Cell-cycle Arrest

MTT and SRB assays were applied to measure the effects of tanshinone A on cell viability. Cell-cycle distribution and apoptosis were assessed via flow cytometry using PI staining and the Annexin V/PI double staining method respectively. Changes to mitochondrial membrane potential was also detected by flow cytometry. The spectrophotometric method was utilized to detect changes of caspase-3 activity. Western blotting assay was used to evaluate the expression of Bcl-2, Bax and c-Myc proteins.

Results indicated that Tan-IIA displayed significant inhibitory effect on the growth of K562 cells in a dose- and time- dependent manner, and displayed only minimal damage to hepatic LO2 cells.

Tan-IIA could arrest K562 cells in the G0/G1 phase and induce apoptosis, decrease mitochondrial transmembrane potential, and the expressions of Bcl-2 and c-Myc proteins, increase the expression of Bax protein and activity of caspase-3. Accordingly, it was presumed that the induction of apoptosis may be through the endogenous pathway. Subsequently, tanshinone A could be a promising candidate in the development of a novel anti-tumor agent (Zhen et al., 2011).

Prostate Cancer, Chemo-sensitizer

Treatment with a combination of Chinese herbs and cytotoxic chemotherapies has shown a higher survival rate in clinical trials.

Tan-IIA displayed synergistic anti-tumor effects on human prostate cancer PC3 cells and LNCaP cells, when combined with cisplatin in vitro. Anti-proliferative effects were detected via MTT assay. Cell-cycle distribution and apoptosis were detected by flow cytometer. Protein expression was detected by Western blotting. The intracellular concentration of cisplatin was detected by high performance liquid chromatography (HPLC).

Results demonstrated that tanshinone II A significantly enhanced the anti-proliferative effects of cisplatin on human prostate cancer PC3 cells and LNCaP cells with an increase in the intracellular concentration of cisplatin. These effects were correlated with cell-cycle arrest at the S phase and induction of cell apoptosis. Apoptosis could potentially be achieved through the death receptor and mitochondrial pathways, decreased expression of Bcl-2.

Collectively, results indicated that the combination of tanshinone II A and cisplatin had a better treatment effect, in vitro, not only on androgen-dependent LNCaP cells but also on androgen-independent PC3 cells (Hou, Xu, Hu, & Xie, 2013).

Autophagic Cell Death, CSCs

Tan IIA significantly increased the expression of microtubule-associated protein light chain 3 (LC3) II as a hallmark of autophagy in Western blotting and immunofluorescence staining. Tan IIA augmented the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and attenuated the phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6K in a dose-dependent manner.Tan IIA dramatically activated the extracellular signal regulated kinase (ERK) signaling pathway including Raf, ERK and p90 RSK in a dose-dependent and time-dependent manner. Consistently, ERK inhibitor PD184352 suppressed LC3-II activation induced by Tan IIA, whereas PD184352 and PD98059 did not affect poly (ADP-ribose) polymerase cleavage and sub-G1 accumulation induced by Tan IIA in KBM-5 leukemia cells.

Tan IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 cells as a potent natural compound for leukemia treatment (Yun et al., 2013).

Cancer stem cells (CSCs) are maintained by inflammatory cytokines and signaling pathways. Tanshinone IIA (Tan-IIA) possesses anti-cancer and anti-inflammatory activities. The purpose of this study is to confirm the growth inhibition effect of Tan-IIA on human breast CSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. After Tan-IIA treatment, cell proliferation and mammosphere formation of CSCs were decreased significantly; the expression levels of IL-6, STAT3, phospho-STAT3 (Tyr705), NF-κBp65 in nucleus and cyclin D1 proteins were decreased significantly; the tumor growth and mean tumor weight were reduced significantly.

Tan-IIA has the potential to target and kill CSCs, and can inhibit human breast CSCs growth both in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways (Lin et al., 2013).

Colorectal Cancer

Tan II-A can effectively inhibit tumor growth and angiogenesis of human colorectal cancer via inhibiting the expression level of COX-2 and VEGF. Angiogenesis plays a significant role in colorectal cancer (CRC) and cyclooxygenase-2 (COX-2) appears to be involved with multiple aspects of CRC angiogenesis (Zhou et al., 2012). The results showed that Tan IIA inhibited the proliferation of inflammation-related colon cancer cells HCT116 and HT-29 by decreasing the production of inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which are generated by macrophage RAW264.7 cell line.

Treatment with TanshinoneIIA prevented increased PU.1, a transcriptional activator of miR-155, and hence increased miR-155, whereas aspirin could not. These findings support that the interruption of signal conduction between activated macrophages and colon cancer cells could be considered as a new therapeutic strategy and miR-155 could be a potential target for the prevention of inflammation-related cancer (Tu et al., 2012).

Breast Cancer

The proliferation rate of T47D and MDA-MB-231 cells influenced by 1×10-6 mol·L-1 and 1×10-7 mol·L-1 Tanshinone IIA was analyzed by MTT assay. Estrogen receptor antagonist ICI182, 780 was employed as a tool. Level of ERα and ERβ mRNA in T47D cells was quantified by Real-time RT-PCR assay. Expression of ERα and ERβ protein was measured by flow cytometry. The proliferation rates of T47D cells treated with Tanshinone IIA decreased significantly. Such effects could be partly blocked by ICI182, 780.

Meanwhile, the proliferation rates of MDA-MB-231 cells treated with Tanshinone IIA decreased much more dramatically. Real-time RT-PCR and flow cytometry results showed that Tanshinone IIA could induce elevation of ERα and ERβ, especially ERα mRNA, and protein expression level in T47D cells. Tanshinone IIA shows inhibitory effects on proliferation of breast cancer cell lines (Zhao et al., 2010).

The role of cell adhesion molecules in the process of inflammation has been studied extensively, and these molecules are critical components of carcinogenesis and cancer metastasis. This study investigated the effect of tanshinone I on cancer growth, invasion and angiogenesis on human breast cancer cells MDA-MB-231, both in vitro and in vivo. Tanshinone I dose-dependently inhibited ICAM-1 and VCAM-1 expressions in human umbilical vein endothelial cells (HUVECs) that were stimulated with TNF-α for 6 h.

Additionally, reduction of tumor mass volume and decrease of metastasis incidents by tanshinone I were observed in vivo. In conclusion, this study provides a potential mechanism for the anti-cancer effect of tanshinone I on breast cancer cells, suggesting that tanshinone I may serve as an effective drug for the treatment of breast cancer (Nizamutdinova et al., 2008).

Nasopharyngeal Carcinoma

To investigate anti-cancer effect and potential mechanism of tanshinone II(A) (Tan II(A)) on human nasopharyngeal carcinoma cell line CNE cells, the anti-proliferative effect of Tan II(A) on CNE cells was evaluated by morphological examination, cell growth curves, colonial assay and MTT assay. Tan II(A) could inhibit CNE cell proliferation in dose- and time-dependent manner. After treatment with Tan II(A), intracellular Ca2+ concentration of CNE cells was increased, mitochondria membrane potential of the cells was decreased, relative mRNA level of Bad and MT-1A was up-regulated. Tan II(A) had an anti-cancer effect on CNE cells through apoptosis via a calcineurin-dependent pathway and MT-1A down-regulation, and may be the next generation of chemotherapy (Dai et al., 2011).

References

Chiu SC, Huang SY, Chen SP, et al. (2013). Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo. Prostate Cancer Prostatic Dis. doi: 10.1038/pcan.2013.38.


Dai Z, Huang D, Shi J, Yu L, Wu Q, Xu Q. (2011). Apoptosis inducing effect of tanshinone II(A) on human nasopharyngeal carcinoma CNE cells. Zhongguo Zhong Yao Za Zhi, 36(15):2129-33.


Hou LL, Xu QJ, Hu GQ, Xie SQ. (2013). Synergistic anti-tumor effects of tanshinone II A in combination with cisplatin via apoptosis in the prostate cancer cells. Acta Pharmaceutica Sinica, 48(5), 675-679.


Lin C, Wang L, Wang H, et al. (2013). Tanshinone IIA inhibits breast cancer stem cells growth in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways. J Cell Biochem, 114(9):2061-70. doi: 10.1002/jcb.24553.


Liu JJ, Zhang Y, Lin DJ, Xiao RZ. (2009). Tanshinone IIA inhibits leukemia THP-1 cell growth by induction of apoptosis. Oncol Rep, 21(4):1075-81.


Nizamutdinova IT, Lee GW, Lee JS, et al. (2008). Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis, 29(10):1885-1892. doi:10.1093/carcin/bgn151


Qiu F, Jiang J, Ma Ym, et al. (2013). Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers. Evidence-Based Complementary and Alternative Medicine, 2013(2013) http://dx.doi.org/10.1155/2013/730734


Tu J, Xing Y, Guo Y, et al. (2012). TanshinoneIIA ameliorates inflammatory microenvironment of colon cancer cells via repression of microRNA-155. Int Immunopharmacol, 14(4):353-61. doi: 10.1016/j.intimp.2012.08.015.


Xu M, Cao FL, Li NY, et al. (2013). Tanshinone IIA reverses the malignant phenotype of SGC7901 gastric cancer cells. Asian Pac J Cancer Prev, 14(1):173-7.


Xu S, Liu P. (2013). Tanshinone II-A: new perspectives for old remedies. Expert Opin Ther Pat, 23(2):149-53. doi: 10.1517/13543776.2013.743995.


Yun SM, Jung JH, Jeong SJ, et al. (2013). Tanshinone IIA Induces Autophagic Cell Death via Activation of AMPK and ERK and Inhibition of mTOR and p70 S6K in KBM-5 Leukemia Cells. Phytother Res. doi: 10.1002/ptr.5015.


Zhen X, Cen J, Li YM, Yan F, Guan T, Tang, XZ. (2011). Cytotoxic effect and apoptotic mechanism of tanshinone A, a novel tanshinone derivative, on human erythroleukemic K562 cells. European Journal of Pharmacology, 667(1-3), 129-135. doi: 10.1016/j.ejphar.2011.06.004.


Zhao PW, Niu JZ, Wang JF, Hao QX, Yu J, et al. (2010). Research on the inhibitory effect of Tanshinone IIA on breast cancer cell proliferation. Zhong Guo Yao Li Xue Tong Bao, 26(7):903-906.


Zhou LH, Hu Q, Sui H, et al. (2012). Tanshinone II–a inhibits angiogenesis through down regulation of COX-2 in human colorectal cancer. Asian Pac J Cancer Prev, 13(9):4453-8.

Akt, angiogenesis, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, Apoptotic, Bcl-xL, Breast cancer, BxPC-3, c-Jun, CCNE2, CDK, CDK2, CDK4, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-sensitizer, chemo-sensitizing, chemo-sensitzer, Colon Cancer or Colorectal cancer, COX-2, CSCs, EpCAM, G1, G2/M, hepato-protective, HT-29, IKK, IL-6, Immunomodulatory, including Terminalia chebula, inflammation, inhibits VEGF, iNOS, JNK, Lung cancer, Mcl-1, Ovarian cancer, p53, p65, Pancreatic cancer, Pro-apoptotic, Radio-protective, Radio-sensitizer, ROS, TAM resistance, TNF, VEGF, VEGF

Luteolin

Cancer: Colorectal., ovarian, pancreatic

Action: Anti-inflammatory, immunomodulatory, radio-sensitizer, chemo-sensitizer

Luteolin is a flavonoid found in many plants and foods, including Terminalia chebula (Retz.), Prunella vulgaris (L.) and Perilla frutescens [(L.) Britton].

Luteolin is contained in Ocimum sanctum L . or Ocimum tenuiflorum L , commonly known as Holy Basil in English or Tulsi in various Indian languages, which is an important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia. Scientific studies have shown it to possess anti-inflammatory, analgesic, anti-pyretic, anti-diabetic, hepato-protective, hypolipidemic, anti-stress, and immunomodulatory activities. It has been found to prevent chemical-induced skin, liver, oral., and lung cancers and mediates these effects by increasing the anti-oxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis.

Colon Cancer

Luteolin inhibited cyclin-dependent kinase (CDK)4 and CDK2 activity, resulting in G1 arrest with a concomitant decrease of phosphorylation of retinoblastoma protein. Activities of CDK4 and CDK2 decreased within 2 hours after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 µmol/l luteolin. Luteolin also promoted G2/M arrest at 24 hours post-treatment by down-regulating cyclin B1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21CIP1/WAF1, survivin, Mcl-1, Bcl-xL, and Mdm-2. Lim et al. (2007) demonstrated that luteolin promotes both cell-cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its anti-tumorigenic activities.

Radio-protective

The aqueous extract of Perilla frutescens has been shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. The chemo-preventive and radio-protective properties of Perilla emphasize aspects that warrant future research to establish its activity and utility in cancer prevention and treatment (Baliga et al., 2013).

Anti-inflammatory

Pre-treatment of RAW 264.7 macrophages with luteolin, luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-α and interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-α release. From the compounds tested, luteolin and quercetin were the most potent in inhibiting cytokine production with an IC50 of less than 1 and 5 µM for TNF-α release, respectively. Moreover, luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IκB-α phosphorylation and reduced the levels of IκB-α. Pre-treatment of cells with luteolin abolished the effects of LPS on IκB-α.

Xagorari et al. (2001) concluded that luteolin inhibits protein tyrosine phosphorylation, nuclear factor-κB-mediated gene expression and pro-inflammatory cytokine production in murine macrophages.

Anti-inflammatory; Neuroinflammation

Pre-treatment of primary murine microglia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of IκB-α but inhibited JNK phosphorylation.

Luteolin consumption reduced LPS-induced IL-6 in plasma 4 hours after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in the hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation (Jang et al., 2008).

Immunostimulatory and Anti-inflammatory

Luteolin (Lut) possesses significant anti-inflammatory activity in well-established models of acute and chronic inflammation, such as xylene-induced ear edema in mice (ED50= 107 mg/ kg), carrageenin-induced swellingof the ankle, acetic acid-induced pleurisy and croton oil-induced gaseous pouch granuloma in rats. Lut had a marked inhibitory effect on the inflammatory exudation, but did not affect the number of leucocytes. Its combined immunostimulatory and anti-inflammatory activity, and inhibitory effect upon immediate hypersensitive response, provide the pharmacologic bases for the beneficial effects of Lut in the treatment of chronic bronchitis (Chen et al., 1986).

Anti-inflammatory

Luteolin dose-dependently inhibited the expression and production of those inflammatory genes and mediators in macrophages stimulated with lipopolysaccharide (LPS). Semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay further confirmed the suppression of LPS-induced TNF- α, IL-6, iNOS and COX-2 gene expression by luteolin at a transcriptional level. Luteolin also reduced the DNA binding activity of nuclear factor-kappa B (NF-κB) in LPS-activated macrophages.

In addition, luteolin significantly inhibited the LPS-induced DNA binding activity of activating protein-1 (AP-1). It was also found that luteolin attenuated the LPS-mediated protein kinase B (Akt) and IKK phosphorylation, as well as reactive oxygen species (ROS) production. In sum, these data suggest that, by blocking NF-κB and AP-1 activation, luteolin acts to suppress the LPS-elicited inflammatory events in mouse alveolar macrophages, and this effect was mediated, at least in part, by inhibiting the generation of reactive oxygen species. These observations suggest a possible therapeutic application of this agent for treating inflammatory disorders in the lung (Chen et al., 2007).

Pancreatic Cancer; Chemo-enhancing

Simultaneous treatment or pre-treatment (0, 6, 24 and 42h) of flavonoids and chemotherapeutic drugs and various concentrations (0-50µM) were assessed using the MTS cell proliferation assay. Pre-treatment for 24 hours with 13µM of either Apigenin or Luteolin, followed by Gem for 36 h was optimal to inhibit cell proliferation.

Pre-treatment of cells with 11-19µM of either flavonoid for 24 hours resulted in 59%–73% growth inhibition when followed by Gem (10µM, 36 hours). Lut (15µM, 24 hours) pre-treatment followed by Gem (10µM, 36h), significantly decreased protein expression of nuclear GSK-3β and NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of Lut effectively aid in the anti-proliferative activity of chemotherapeutic drugs (Johnson et al., 2013).

Ovarian Cancer

Recent studies further indicate that luteolin potently inhibits VEGF production and suppresses ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM.

Unlike NSAIDS (non-steroid anti-inflammatory drugs), well-documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Chemo-sensitizer

The sensitization effect of luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to luteolin and cisplatin. The critical role of c-Jun NH(2)-terminal kinase (JNK) was identified in regulation of p53 protein stability: luteolin activates JNK, and JNK then stabilizes p53 via phosphorylation, leading to reduced ubiquitination and proteasomal degradation.

An in vivo nude mice xenograft model confirmed that luteolin enhanced the cancer therapeutic activity of cisplatin via p53 stabilization and accumulation. In summary, data from this study reveal a novel molecular mechanism involved in the anti-cancer effects of luteolin and support its potential clinical application as a chemo-sensitizer in cancer therapy (Shi et al., 2007).

Breast Cancer; Chemo-sensitzer

Luteolin is a flavonoid that has been identified in many plant tissues and exhibits chemo-preventive or chemo-sensitizing properties against human breast cancer. However, the oncogenic molecules in human breast cancer cells that are inhibited by luteolin treatment have not been identified.

Relatively high levels of cyclin E2 (CCNE2) protein expression were detected in tamoxifen-resistant (TAM-R) MCF-7 cells. These results showed that the level of CCNE2 protein expression was specifically inhibited in luteolin-treated (5µM) TAM-R cells, either in the presence or absence of 4-OH-TAM (100nM). Combined treatment with 4-OH-TAM and luteolin synergistically sensitized the TAM-R cells to 4-OH-TAM. The results of this study suggest that luteolin can be used as a chemo-sensitizer to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients (Tu et al., 2013).

References

Baliga MS, Jimmy R, Thilakchand KR, et al. (2013). Ocimum sanctum L (Holy Basil or Tulsi) and its phytochemicals in the prevention and treatment of cancer. Nutr Cancer, 65(1):26-35. doi: 10.1080/01635581.2013.785010.

Chen CY, Peng WH, Tsai KD and Hsu SL. (2007). Luteolin suppresses inflammation-associated gene expression by blocking NF- κ B and AP-1 activation pathway in mouse alveolar macrophages. Life Sciences, 81(23-24):1602-1614. doi:10.1016/j.lfs.2007.09.028

Chen MZ, Jin WZ, Dai LM, Xu SY. (1986). Effect of luteolin on inflammation and immune function. Chinese Journal of Pharmacology and Toxicology, 1986-01.

Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.

Jang S, Kelley KW, Johnson RW. (2008). Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. PNAS, 105(21):7534-7539

Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, S0278-6915(13)00491-2. doi: 10.1016/j.fct.2013.07.036.

Lim DY, Jeong Y, Tyner Al., Park JHY. (2007). Induction of cell-cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol, 292: G66-G75. doi:10.1152/ajpgi.00248.2006.

Shi R, Huang Q, Zhu X, et al. (2007). Luteolin sensitizes the anti-cancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Molecular Cancer Therapeutics, 6(4):1338-1347. doi: 10.1158/1535-7163.MCT-06-0638.

Tu SH, Ho CT, Liu MF, et al. (2013). Luteolin sensitizes drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem, 141(2):1553-61. doi: 10.1016/j.foodchem.2013.04.077.

Xagorari A, Papapetropoulos A, Mauromatis A, et al. (2001). Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and pro-inflammatory cytokine production in macrophages. JPET, 296(1):181-187.

Akt, angiogenesis, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-proliferative, apoptosis, Apoptotic, ARO, Autophagy, Autophagy inhibitor, BAX, Bcl-2, Breast cancer, Breast cancer cell lines, CDK6, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, cytotoxic, Depression or Anxiety, Down-regulates, DU145 and PC3, ER, ER-negative, Evodia rutaecarpa, G0/G1, G1, G2/M, IKK, increases intracellular ROS, inflammation, inhibits metastasis, inhibits NF-κB, Lung cancer, MCF-7 and MDA-MB-231, MDR, MTOR, Nitric Oxide, Pancreatic cancer, PI3K, PI3K/Akt, PTEN, ROS, SGC7901, TNF

Evodiamine

Cancer: Pancreatic, gastric, breast; ER+, ER-, lung

Action: Inhibits NF- κB, inhibits metastasis, increases intracellular ROS, apoptosis, cell-cycle arrest, anti-cancer, MDR

Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodia rutaecarpa [(Juss.) Benth.] (alkaloidal component of the extract). With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and thermo-regulative effects. Evodiamine has evolved a superior ability to bind various proteins (Yu et al., 2013). Evodiamine exhibits anti-proliferative, anti-metastatic, and apoptotic activities.

Anti-cancer, MDR

Evodiamine possesses anti-anxiety, anti-obesity, anti-nociceptive, anti-inflammatory, anti-allergic, and anti-cancer effects. As well, it has thermoregulation, protection of myocardial ischemia-reperfusion injury and vessel-relaxing activities (Kobayashi, 2003; Shin et al., 2007; Ko et al., 2007; Ji, 2011). Evodiamine exhibits anti-cancer activities both in vitro and in vivo by inducing cell-cycle arrest or apoptosis, and inhibiting angiogenesis, invasion, and metastasis in a variety of cancer cell lines (Ogasawara et al., 2001; Ogasawara et al., 2002; Fei et al., 2003; Shyu et al., 2006). It presents anti-cancer potentials at micromolar concentrations and even at the nanomolar level in some cell lines in vitro (Lee et al., 2006; Wang, Li, & Wang, 2010). Evodiamine also stimulates autophagy, which serves as a survival function (Yang et al., 2008). Compared with other compounds, evodiamine is less toxic to normal human cells, such as human peripheral blood mononuclear cells (Fei et al., 2003; Zhang et al., 2004). It also inhibits the proliferation of adriamycin-resistant human breast cancer NCI/ADR-RES cells both in vitro and in Balb-c/nude mice (Liao et al., 2005).

Lung Cancer, Cell-cycle Arrest

Evodiamine (10  mg/kg) administrated orally twice daily significantly inhibits   tumor growth (Liao et al., 2005). Moreover, treatment with 10 mg/kg evodiamine from the 6th day after tumor inoculation into mice reduces lung metastasis and does not affect the body weight of mice during the experimental period (Ogasawara et al., 2001).

Cell-cycle Arrest

Evodiamine inhibits TopI enzyme, forms the DNA covalent complex with a similar concentration to that of irinotecan, and induces DNA damage (Chan et al., 2009; Tsai et al., 2010; Dong et al., 2010). However, TopI may not be the main target of this compound. Cancer cells treated with evodiamine exhibit G 2 / M phase arrest (Kan et al., 2004; Huang et al., 2004; Liao et al., 2005) rather than S phase arrest, which is not consistent with the mechanism of classic TopI inhibitors, such as irinotecan. Therefore, other targets aside from TopI may also be important for realizing the anti-cancer potentials of evodiamine. This statement is supported by the fact that evodiamine has effects on tubulin polymerization (Huang et al., 2004).

Increases Intracellular ROS, Apoptosis

Exposure to evodiamine rapidly increases intracellular ROS followed by an onset of mitochondrial depolarization (Yang et al., 2007). The generation of ROS and nitric oxide acts in synergy and triggers mitochondria-dependent apoptosis (Yang et al., 2008). Evodiamine also induces caspase-dependent and caspase-independent apoptosis, down-regulates Bcl-2 expression, and up-regulates Bax expression in some cancer cells (Zhang et al., 2003; Lee et al., 2006). The phosphatidylinositol 3-kinase/Akt/caspase and Fas ligand (Fas-L)/NF-κB signaling pathways might account for evodiamine-induced cell death. Moreover, these signals could be increased by the ubiquitin-proteasome pathway (Wang, Li, & Wang, 2010).

Inhibits Metastasis

Evodiamine has a marked inhibitory activity on tumor cell migration in vitro. When evodiamine at 10 mg/kg was administered into mice from the 6th day after tumor inoculation, the number of tumor nodules in lungs was decreased by 48% as compared to control. The inhibition rate was equivalent to that produced by cisplatin. Results suggest that evodiamine may be regarded as a promising agent in tumor metastasis therapy (Ogasawara et al., 2005).

Inhibits NF-κB

Evodiamine inhibited tumor necrosis factor (TNF)-induced Akt activation and its association with IKK. This down-regulation potentiated the apoptosis induced by cytokines and chemotherapeutic agents and suppressed TNF-induced invasive activity. Overall, these results indicate that evodiamine inhibits both constitutive and induced NF-κB activation and NF-κB-regulated gene expression (Takada et al., 2005).

Breast Cancer

Endocrine sensitivity, assessed by the expression of estrogen receptor (ER), has long been the predict factor to guide therapeutic decisions. Tamoxifen has been the most successful hormonal treatment in endocrine-sensitive breast cancer. However, in estrogen-insensitive cancer tamoxifen showed less effectiveness than in estrogen-sensitive cancer. It is interesting to develop new drugs against both hormone-sensitive and insensitive tumor. In this present study Wang et al. (2013) examined anti-cancer effects of evodiamine extracted from the Chinese herb, Evodiae fructus, in estrogen-dependent and -independent human breast cancer cells, MCF-7 and MDA-MB-231 cells, respectively.

Breast Cancer; ER+, ER-

The expression of ER α and β in protein and mRNA levels was down-regulated by evodiamine according to data from immunoblotting and RT-PCR analysis. Overall, results indicate that evodiamine mediates degradation of ER and induces caspase-dependent pathway leading to inhibition of proliferation of breast cancer cell lines. It suggests that evodiamine may in part mediate through ER-inhibitory pathway to inhibit breast cancer cell proliferation.

Evodiamine (10 mg/kg) significantly reduced tumor growth and pulmonary metastasis. In vitro, evodiamine inhibited cell migration and invasion abilities through down-regulation of MMP-9, urokinase-type plasminogen activator (uPA) and uPAR expression. Evodiamine-induced G0/G1 arrest and apoptosis were associated with a decrease in Bcl-2, cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression and an increase in Bax and p27Kip1 expression (Du et al., 201).

Gastric Cancer

A study by Rasul et al. (2012) was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. Evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell-cycle arrest.

Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Evodiamine has therapeutic potential against cancers.

Pancreatic Cancer

In vitro application of the combination therapy triggered significantly higher frequency of pancreatic cancer cells apoptosis, inhibited the activities of PI3K, Akt, PKA, mTOR and PTEN, and decreased the activation of NF-κB and expression of NF- κB-regulated products. Evodiamine can augment the therapeutic effect of gemcitabine in pancreatic cancer through direct or indirect negative regulation of the PI3K/Akt pathway (Wei et al., 2012).

References

Chan ALF, Chang WS, Chen LM et al. (2009). Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit topoisomerase I activity. Molecules, (14):4:1342–1352.


Dong G, Sheng C, Wang CS, et al. (2010). Selection of evodiamine as a novel topoisomerase i inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as anti-tumor agents. Journal of Medicinal Chemistry, 53(21):7521–7531.


Du J, Wang XF, Zhou QM, et al. (2013). Evodiamine induces apoptosis and inhibits metastasis in MDA “American Typewriter”; “American Typewriter”;‑ MB-231 human breast cancer cells in vitro and in vivo. Oncol Rep, 30(2):685-94. doi: 10.3892/or.2013.2498.


Fei XF, Wang BX, T. Li TJ et al. (2003). Evodiamine, a constituent of Evodiae Fructus, induces anti-proliferating effects in tumor cells. Cancer Science, 94(1):92–98.


Huang YC, Guh JH, Teng CM. (2004). Induction of mitotic arrest and apoptosis by evodiamine in human leukemic T-lymphocytes. Life Sciences, 75(1):35–49.


Ji YB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application. People's Medical Publishing House Co., LTD. Connecticut USA


Kan SF, Huang WJ, Lin LC, Wang PS. (2004). Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP. International Journal of Cancer, 110(5):641–651.


Ko HC, Wang YH, Liou KT et al. (2007). Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells. European Journal of Pharmacology, 555(2-3):211–217.


Kobayashi Y. (2003). The nociceptive and anti-nociceptive effects of evodiamine from fruits of Evodia rutaecarpa in mice. Planta Medica, 69(5):425–428.


Lee TJ, Kim EJ, Kim S et al. (2006). Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells. Molecular Cancer Therapeutics, 5(9):2398–2407.


Liao CH, Pan SL, Guh JH et al. (2005). Anti-tumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo. Carcinogenesis, 26(5):968–975.


Ogasawara M, Matsubara T, Suzuki H. (2001). Inhibitory effects of evodiamine on in vitro invasion and experimental lung metastasis of murine colon cancer cells. Biological and Pharmaceutical Bulletin, 24(8):917–920.


Ogasawara M, Matsunaga T, Takahashi S, Saiki I, Suzuki H. (2002). Anti-invasive and metastatic activities of evodiamine. Biological and Pharmaceutical Bulletin, 25(11):1491–1493.


Rasul A, Yu B, Zhong L, et al. (2012). Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy. Oncol Rep, 27(5):1481-7. doi: 10.3892/or.2012.1694


Shin YW, Bae EA, Cai XF, Lee JJ, and Kim DH. (2007). In vitro and in vivo antiallergic effect of the fructus of Evodia rutaecarpa and its constituents, Biological and Pharmaceutical Bulletin, 30(1):197–199, 2007.


Shyu KG, Lin S, Lee CC et al. (2006). Evodiamine inhibits in vitro angiogenesis: implication for anti-tumorgenicity. Life Sciences, 78(19):2234–2243.


Takada Y, Kobayashi Y, Aggarwal BB. (2005). Evodiamine Abolishes Constitutive and Inducible NF- κB Activation by Inhibiting IκBα Kinase Activation, Thereby Suppressing NF-κ B-regulated Antiapoptotic and Metastatic Gene Expression, Up-regulating Apoptosis, and Inhibiting Invasion. The Journal of Biological Chemistry, 280:17203-17212. doi: 10.1074/jbc.M500077200.


Tsai HP, Lin LW, Lai ZY et al. (2010). Immobilizing topoisomerase I on a surface plasmon resonance biosensor chip to screen for inhibitors. Journal of Biomedical Science, 17(1):49.


Wang C, Li S, Wang MW. (2010). Evodiamine-induced human melanoma A375-S2 cell death was mediated by PI3K/Akt/caspase and Fas-L/NF- κ B signaling pathways and augmented by ubiquitin-proteasome inhibition. Toxicology in Vitro, 24(3):898–904.


Wang KL, Hsia SM, Yeh JY, et al. (2013). Anti-Proliferative Effects of Evodiamine on Human Breast Cancer Cells. PLoS One, 8(6):e67297.


Wei WT, Chen H, Wang ZH, et al. (2012). Enhanced anti-tumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway. Int J Biol Sci, 8(1):1-14.


Yu H, Jin H, Gong W, Wang Z, Liang H. (2013). Pharmacological actions of multi-target-directed evodiamine. Molecules, 18(2):1826-43. doi: 10.3390/molecules18021826.


Yang J, Wu LJ, Tashino SI, et al. (2007). Critical roles of reactive oxygen species in mitochondrial permeability transition in mediating evodiamine-induced human melanoma A375-S2 cell apoptosis. Free Radical Research, 41(10):1099–1108.


Zhang Y, Wu LJ, Tashiro SI, Onodera S, Ikejima T. (2003). Intracellular regulation of evodiamine-induced A375-S2 cell death. Biological and Pharmaceutical Bulletin, 26(11):1543–1547.


Zhang Y, Zhang QH, Wu LJ, et al. (2004). Atypical apoptosis in L929 cells induced by evodiamine isolated from Evodia rutaecarpa. Journal of Asian Natural Products Research, 6(1):19–27.

A2780, A549, Akt, angiogenesis, Anti-cancer, anti-metastasis, Anti-metastatic, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tubulin, anti-tumor, Apo2L, Apo2L/TRAIL, apoptosis, Apoptotic, Breast cancer, BxPC-3, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-sensitizer, Colon Cancer or Colorectal cancer, Down-regulates, down-regulates MMP-9, DR5, DU145, ER, G2/M, induces apoptosis, inhibits angiogenesis, inhibits proliferation, Lung cancer, MDA-MB-231, MDA-MB-453, metastasis, Ovarian cancer, Pancreatic cancer, Pro-apoptotic, Prostate cancer, Rectal cancer, SW480, DLD-1, LS174T, TAGLN, TRAIL, various fruits, vegetables

Apigenin

Cancer:
Breast, gastrointestinal., prostate, ovarian, pancreatic

Action: Anti-proliferative effect, induces apoptosis, chemo-sensitizer

Apigenin (4′,5,7-trihydroxyflavone, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many fruits, vegetables, and herbs, the most abundant sources being the leafy herb parsley and dried flowers of chamomile. Present in dietary sources as a glycoside, it is cleaved in the gastrointestinal lumen to be absorbed and distributed as apigenin itself. For this reason, the epithelium of the gastrointestinal tract is exposed to higher concentrations of apigenin than tissues at other locations. This would also be true for epithelial cancers of the gastrointestinal tract. There is evidence that the actions of apigenin might hinder the ability of gastrointestinal cancers to progress and spread.

Induces Apoptosis, Anti-metastatic

Apigenin has been shown to inhibit cell growth, sensitize cancer cells to elimination by apoptosis, and hinder the development of blood vessels to serve the growing tumor. It also has actions that alter the relationship of the cancer cells with their microenvironment. Apigenin is able to reduce cancer cell glucose uptake, inhibit remodeling of the extracellular matrix, inhibit cell adhesion molecules that participate in cancer progression, and oppose chemokine signaling pathways that direct the course of metastasis into other locations. As such, apigenin may provide some additional benefit beyond existing drugs in slowing the emergence of metastatic disease (Lefort, 2013).

Chemo-sensitizer, Induces Apoptosis

Choi & Kim (2009) investigated the effects of combined treatment with 5-fluorouracil and apigenin on proliferation and apoptosis, as well as the underlying mechanism, in human breast cancer MDA-MB-453 cells. The MDA-MB-453 cells, which have been shown to overexpress ErbB2, were resistant to 5-fluorouracil; 5-fluorouracil exhibited a small dose-dependent anti-proliferative effect, with an IC50 of 90 microM. Interestingly, combined treatment with apigenin significantly decreased the resistance. Cellular proliferation was significantly inhibited in cells exposed to 5-fluorouracil at its IC50 and apigenin (5, 10, 50 and 100 microM), compared with proliferation in cells exposed to 5-fluorouracil alone.

This inhibition in turn led to apoptosis, as evidenced by an increased number of apoptotic cells and the activation of caspase-3. Moreover, compared with 5-fluorouracil alone, 5-fluorouracil in combination with apigenin at concentrations >10 microM exerted a pro-apoptotic effect via the inhibition of Akt expression.

Taken together, results suggest that 5-fluorouracil acts synergistically with apigenin inhibiting cell growth and inducing apoptosis via the down-regulation of ErbB2 expression and Akt signaling (Choi, 2009).

Breast Cancer, Prostate Cancer

Two flavonoids, genistein and apigenin, have been implicated as chemo-preventive agents against prostate and breast cancers; however, the mechanisms behind their respective cancer-protective effects may vary significantly. It was thought that the anti-proliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) β is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17β-estradiol, exhibited anti-proliferative effects and pro-apoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERβ transactivation, particularly at lower concentrations.

However, in mammalian assay, apigenin was found to be more ERβ-selective than genistein, which has equal potency in inducing transactivation through ERα and ERβ. Small interfering RNA-mediated down-regulation of ERβ abrogated the anti-proliferative effect of apigenin in both cancer cells but did not reverse that of genistein. These results unveil that the anti-cancer action of apigenin is mediated, in part, by ERβ. The differential use of ERα and ERβ signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anti-cancer properties (Mak, 2006).

Ovarian Cancer

Id1 (inhibitor of differentiation or DNA binding protein 1) contributes to tumorigenesis by stimulating cell proliferation, inhibiting cell differentiation and facilitating tumor neoangiogenesis. Elevated Id1 is found in ovarian cancers and its level correlates with the malignant potential of ovarian tumors. Therefore, Id1 is a potential target for ovarian cancer treatment. It has been demonstrated that apigenin inhibits proliferation and tumorigenesis of human ovarian cancer A2780 cells through Id1. Apigenin has been found to suppress the expression of Id1 through activating transcription factor 3 (ATF3). These results may elucidate a new mechanism underlying the inhibitory effects of apigenin on cancer cells (Li, 2009).

Pancreatic Cancer

Simultaneous treatment or pre-treatment (0, 6, 24 and 42 hours) of apigenin and chemotherapeutic drugs and various concentrations (0-50µM) were assessed using the MTS cell proliferation assay. Simultaneous treatment with apigenin (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60 hours resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of apigenin, followed by Gem for 36 hours was optimal to inhibit cell proliferation.

Pre-treatment of cells with 11-19µM of apigenin for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of apigenin hence effectively aids in the anti-proliferative activity of chemotherapeutic drugs (Johnson, 2013).

Induces Apoptosis, Inhibits Angiogenesis and Metastasis.

Preclinical studies have also shown that Ocimum sanctum L. and some of the phytochemicals it contains (including apigenin) prevents chemical-induced skin, liver, oral., and lung cancers. These effects are thought to be mediated by increasing the anti-oxidant activity, altering gene expression, inducing apoptosis, and inhibiting angiogenesis and metastasis. The aqueous extract of Ocimum sanctum L. has been shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. In particular, important phytochemicals like apigenin have also been shown to prevent radiation-induced DNA damage. This warrants its future research to establish its activity and utility in cancer prevention and treatment (Baliga, 2013).

Lung Cancer

Apigenin has been found to induce apoptosis and cell death in lung epithelium cancer (A549) cells with an IC50 value of 93.7 ± 3.7 µM for 48 hours treatment. Target identification investigations using A549 cells and in cell-free systems demonstrate that apigenin depolymerized microtubules and inhibited reassembly of cold depolymerized microtubules of A549 cells. Again apigenin inhibited polymerization of purified tubulin with an IC50 value of 79.8 ± 2.4 µM. Interestingly, apigenin also showed synergistic anti-cancer effects with another natural anti-tubulin agent, curcumin. Apigenin and curcumin synergistically induce cell death and apoptosis and also block cell-cycle progression at G2/M phase of A549 cells.

Understanding the mechanism of the synergistic effect of apigenin and curcumin could help to develop anti-cancer combination drugs from cheap and readily available nutraceuticals (Choudhury, 2013).

Induces Apoptosis

It has been shown that the dietary flavonoid apigenin binds and inhibits adenine nucleotide translocase-2 (ANT2), resulting in enhancement of Apo2L/TRAIL-induced apoptosis by up-regulation of DR5, making it a potential cancer therapeutic agent. Apigenin has been found to enhance Apo2L/TRAIL-induced apoptosis in cancer cells by inducing DR5 expression through binding ANT2. Similarly to apigenin, knockdown of ANT2 enhanced Apo2L/TRAIL-induced apoptosis by up-regulating DR5 expression at the post-transcriptional level.

Moreover, silencing of ANT2 attenuated the enhancement of Apo2L/TRAIL-induced apoptosis by apigenin. These results suggest that apigenin Up-regulates DR5 and enhances Apo2L/TRAIL-induced apoptosis by binding and inhibiting ANT2. ANT2 inhibitors like apigenin may hence contribute to Apo2L/TRAIL therapy (Oishi, 2013).

Colorectal Cancer

Apigenin has anti-proliferation, anti-invasion and anti-migration effects in three kinds of colorectal adenocarcinoma cell lines, namely SW480, DLD-1 and LS174T. Proteomic analysis with SW480 indicated that apigenin up-regulated the expression of transgelin (TAGLN) in mitochondria to exert its anti-tumor growth and anti-metastasis effects. Apigenin decreased the expression of MMP-9 in a dose-dependent manner. Transfection of three truncated forms of TAGLN and wild type has identified TAGLN as a repressor of MMP-9 expression.

This research provides direct evidence that apigenin inhibits tumor growth and metastasis both in vitro and in vivo. Apigenin up-regulates TAGLN and down-regulates MMP-9 expression through decreasing phosphorylation of Akt at Ser473 and in particular Thr308 to prevent cancer cell proliferation and migration (Chunhua, 2013).

References

Baliga MS, Jimmy R, Thilakchand KR, et al. (2013). Ocimum Sanctum L (Holy Basil or Tulsi) and Its Phytochemicals in the Prevention and Treatment of Cancer. Nutr Cancer, 65(1):26-35. doi: 10.1080/01635581.2013.785010.

 

 

Choi EJ, Kim GH. (2009). 5-Fluorouracil combined with apigenin enhances anti-cancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep, 22(6):1533-7.

 

Choudhury D, Ganguli A, Dastidar DG, et al. (2013). Apigenin shows synergistic anti-cancer activity with curcumin by binding at different sites of tubulin. Biochimie, 95(6):1297-309. doi: 10.1016/j.biochi.2013.02.010.

 

Chunhua L, Donglan L, Xiuqiong F, et al. (2013). Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT. J Nutr Biochem. doi: 10.1016/j.jnutbio.2013.03.006.

 

Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, 20:83-91. doi: 10.1016/j.fct.2013.07.036.

 


Lefort ƒC, Blay J. (2013). Apigenin and its impact on gastrointestinal cancers. Mol Nutr Food Res, 57(1):126-44. doi: 10.1002/mnfr.201200424.

 

Li ZD, Hu XW, Wang YT & Fang J. (2009). Apigenin inhibits proliferation of ovarian cancer A2780 cells through Id1. FEBS Letters, 583(12):1999-2003 doi:10.1016/j.febslet.2009.05.013.

 

Mak P, Leung YK, Tang WY, Harwood C & Ho SM. (2006). Apigenin suppresses cancer cell growth through ERβ. Neoplasia, 8(11):896–904.

 

Oishi M, Iizumi Y, Taniguchi T, et al. (2013). Apigenin Sensitizes Prostate Cancer Cells to Apo2L/TRAIL by Targeting Adenine Nucleotide Translocase-2. PLoS One, 8(2):e55922. doi: 10.1371/journal.pone.0055922.