Category Archives: anti-tumor

Akt, angiogenesis, Anti-cancer, anti-inflammatory, anti-tumor, apoptosis, Apoptotic, Bcl-2, cancer stem cells, Cervical cancer, Chapter 7 Isolates and Cancer Research, CSCs, cytotoxic, FoxO1, G2/M, Glioblastoma, IKK, IL-6, metastasis, PARP, Rectal cancer, SHH

Zerumbone

Cancer:
Colorectal, renal carcinoma, glioblastoma, ovarian and cervical

Action: CSCs, anti-inflammatory

Zerumbone is isolated from Zingiber zerumbet [(L.) Roscoe ex Sm.].

Colorectal Cancer

Numerous agents from 'mother nature' (also called nutraceuticals) that have potential to both prevent and treat CRC have been identified. The most significant discoveries relate to compounds such as cardamonin, celastrol, curcumin, deguelin, diosgenin, thymoquinone, tocotrienol, ursolic acid, and zerumbone. Unlike pharmaceutical drugs, these agents modulate multiple targets, including transcription factors, growth factors, tumor cell survival factors, inflammatory pathways, and invasion and angiogenesis linked closely to CRC. We describe the potential of these dietary agents to suppress the growth of human CRC cells in culture and to inhibit tumor growth in animal models (Aggarwal et al., 2013).

Cancer Stem Cells (CSCs)

Cancer stem cells (CSCs) are a major cause of cancer treatment failure, relapse, and drug resistance and are known to be responsible for cancer cell invasion and metastasis. The Sonic hedgehog (Shh) signaling pathway is crucial to embryonic development. Intriguingly, the aberrant activation of the Shh pathway plays a critical role in developing CSCs and leads to angiogenesis, migration, invasion, and metastasis. Natural compounds and chemical structure modified derivatives from complementary and alternative medicine have received increasing attention as cancer chemo-preventives, and their anti-tumor effects have been demonstrated both in vitro and in vivo.

Compounds cyclopamine, curcumin, epigallocatechin-3-gallate, genistein, resveratrol, zerumbone, norcantharidin, and arsenic trioxide, with a focus on Shh signaling blockade, were reviewed by Huang et al. (2013) and given that Shh signaling antagonism has been clinically proven as an effective strategy against CSCs, this review may be exploitable for the development of novel anti-cancer agents from complementary and alternative medicine.

Renal Carcinoma

Sun et al. (2013) reported that zerumbone, a monosesquiterpine, shows anti-cancer effects on human RCC cells via induction of apoptosis in vitro. Human renal clear cell carcinoma 786-0 and 769-P cell lines were used as the model system. Exposure of RCC cells to zerumbone resulted in cell viability inhibition, accompanied by DNA fragmentation and increased apoptotic index. Mechanically, treatment of RCC cells with zerumbone activated caspase-3 and caspase-9 finally led to cleavage of PARR.

Taken together, our studies provided the first evidence that zerumbone imparted strong inhibitory and apoptotic effects on human RCC cells. The zerumbone-induced apoptosis might be related to the activation of the caspase cascade and deregulation of the Gli-1/Bcl-2 pathway. Our results suggest that zerumbone merit further investigation as an apoptosis inducer as well as a novel RCC chemotherapeutic agent in the clinical setting.

Glioblastoma

Zerumbone (10~50 µM) induced death of human glioblastoma multiforme (GBM8401) cells in a dose-dependent manner. Flow cytometry studies showed that zerumbone increased the percentage of apoptotic GBM cells. Zerumbone also caused caspase-3 activation and poly (ADP-ribose) polymerase (PARP) production. N-benzyloxycarbonyl -Val-Ala-Asp- fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor, hindered zerumbone-induced cell death. Moreover, transfection of GBM8401 cells with WT IKKα reduced the zerumbone-induced decrease in Akt and FOXO1 phosphorylation. However, transfection with WT Akt decreased FOXO1, but not IKKα, phosphorylation.

The results suggest that inactivation of IKKα, followed by Akt and FOXO1 phosphorylation and caspase-3 activation, contributes to zerumbone-induced GBM cell apoptosis (Weng et al., 2012).

Ovarian and Cervical Cancer

A study by Abdelwahab et al., (2012) was designed to investigate the role of IL-6 and IL6 receptors in the cytotoxic effects of zerumbone in ovarian and cervical cancer cell lines (Caov-3 and HeLa, respectively). Exposure of both cancer cells to zerumbone or cisplatin demonstrated growth inhibition in a dose-dependent manner as determined by the MTT reduction assay. The studies conducted seem to suggest that zerumbone induces cell death by stimulating apoptosis better than cisplatin, based on the significantly higher percentage of apoptotic cells in zerumbone's treated cancer cells as compared to cisplatin. In addition, zerumbone and cisplatin arrest cancer cells at G2/M phase as analyzed by flow cytometry. These results indicated that zerumbone significantly decreased the levels of IL-6 secreted by both cancer cells.

This study concludes that the compound, zerumbone, inhibits cancer cell growth through the induction of apoptosis, arrests cell-cycle at G2/M phase and inhibits the secretion levels of IL-6 in both cancer cells.

References

Abdelwahab SI, Abdul AB, Zain ZN, Hadi AH. (2012). Zerumbone inhibits interleukin-6 and induces apoptosis and cell-cycle arrest in ovarian and cervical cancer cells. Int Immunopharmacol,12(4):594-602. doi: 10.1016/j.intimp.2012.01.014.


Aggarwal B, Prasad S, Sung B, Krishnan S, Guha S. (2013). Prevention and Treatment of Colorectal Cancer by Natural Agents From Mother Nature. Curr Colorectal Cancer Rep, 9(1):37-56.


Huang YC, Chao KS, Liao HF, Chen YJ. (2013). Targeting sonic hedgehog signaling by compounds and derivatives from natural products. Evid Based Complement Alternat Med, 2013:748587. doi: 10.1155/2013/748587.


Sun Y, Sheng Q, Cheng Y, et al. (2013). Zerumbone induces apoptosis in human renal cell carcinoma via Gli-1/Bcl-2 pathway. Pharmazie, 68(2):141-5.


Weng HY, Hsu MJ, Wang CC, et al. (2012). Zerumbone suppresses IKK α , Akt, and FOXO1 activation, resulting in apoptosis of GBM 8401 cells. J Biomed Sci, 19:86. doi: 10.1186/1423-0127-19-86.

anti-tumor, Chapter 7 Isolates and Cancer Research, Chemotherapy, Gastric cancer or Stomach cancer, Immune, metastasis

Yiqi Bushen Oral Liquid

Cancer: Leukemia, colon, liver, gastric, lung, stomach

Action: Immune

Formula

Astragali Radix (huang qi), Poria (fu ling), Ligustri lucidi Fructus (nu zhen zi), Lycii Fructus (gou qi zi), Sclerotium Polypori Umbellati (zhu ling), Curcumae Rhizoma Ezhu (e zhu), Scutellariae barbatae Herba (ban zhi lian), Actinidiae Chinensis Radix (teng li gen), Coicis Semen (yi ren), Caulis Aristolochiae Manshuriensis (ba yue zha), Jujubae Fructus (da zao), Glycyrrhizae Radix preparata (zhi gan cao)

T-lymphocyte Survival

To study the effect of Yiqi Bushen oral liquid (YQBS) on tumor-infiltrating lymphocytes TIL in vitro and its related immunological mechanism, eparation of T-lymphocytes by discontinuous density gradient centrifugation was used to observe the impaction of YQBS on survival of TIL. YQBS could prolong survival time of TIL significantly and enhanced the killing activity of autologous tumor cells and K562 cells. Moreover, the cell smear and electron microscopy analysis showed that TIL growth increased significantly by culturing about one week. YQBS could increase the growth and the activity of TIL. Notably the mechanism of anti-tumor effects of YQBS might be related to the strengthened immune function of mice (Ruan et al., 2009).

Colon

Fifty four patients with carcinoma of the large intestine, after operation were divided into two groups randomly. In the therapeutic group, we used Yiqi Bushen oral liquid combined with chemotherapy to treat 33 patients, and in the control group, used only chemotherapy to treat 21 patients. The metastatic rate of the therapeutic group was much lower than that of the control group (P<0.05). Compared with the control group, the therapeutic group improved on the Kamofsky score, body weight, and peripheral blood flow (P <0.01).

Yiqi Bushen oral liquid   is effective to resist metastasis and relapse of patients after operation of carcinoma of the large intestine. It additionally has effect on sensitization, attenuation, and quality of life (Liu et al., 2007).

Lung

Viable cell count and MTT staining assay were used to assess the anti-tumor effects of Yiqi Bushen liquid on two kinds of cells. Yiqi Bushen liquid had an inhibitory action on the growth curve of SMMC27721 nude mice xenografts and A549 cells (alveolar basal epithelial cells). The IC50 of the two cells were 1.02mg/mL and 0.73mg/mL respectively. It also inhibited colony formation in both cell lines. The highest inhibitory rates of Yiqibushen liquid against SMMC27721 and A549 cells were 78.48% and 89.17%, respectively. Yiqi Bushen liquid has strong anti-tumor effects in vitro (Ruan et al., 2008).

Stomach Cancer

Forty seven patients with spleen and kidney deficiency syndrome after operation for stomach cancer were randomized into treatment group (n=28) or control group (n=19). The control group was treated simply by chemotherapy and the treatment group by chemotherapy and Yiqi Bushen Oral Liquid.

The relapse and metastatic rate of the treatment group was remarkably lower than that of the control group (P<0.05). The Karnofsky score, peripheral blood and immune function were all remarkably improved in comparison with the control group (P<0.01 or P<0.05). Yiqi Bushen oral liquid, combined with chemotherapy, has an effective function in resisting the metastasis of stomach cancer after operation, increasing chemo-sensitivity, decreasing adverse reactions, improving quality of life, and improving immune function of patients (Liu et al., 2008).

References

Liu YX, Jiang SJ, Kuang TH, Yao YW, Yang JW. (2007). Clinical Observation of Yiqi Bushen Oral Liquid to the Patients with Carcinoma of Large Intestine's Metastasis and Relapse After Operation. Zhong Hua Zhong Yi Yao Xue Kan, 25(5):1072-1073.


Liu YX, Jiang SH, Kuang TH, Yao YW, Yang JW, Wang YQ. (2008). Clinical Observation on 28 Cases of the Metabasis of Stomach Cancer after Operation Treated by Yiqi Bushen Oral Liquid: and Chemotherapy. Zhong Yi Za Zhi, 49(2):128-130.


Ruan YP, Hu XM. (2008). An Experimental Study on Anti- tumor Effects of Yiqi Bushen Liquid in Vitro. Zhong Hua Zhong Yi Yao Xue Kan, 26(11):2445-2446.


Ruan YP, Hu XM, Liu YX, Li FZ. (2009). Research on the effect of Yi Qi Bu Shen oral liquid on tumor-infiltrating lymphocytes in vitro. Dang Dai Yi Xue, 15(4):136-138.

A549, Akt, angiogenesis, Anti-angiogenic, Anti-cancer, Anti-estrogenic, anti-inflammatory, anti-lymphangiogenesis, anti-metastasis, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Breast cancer, c-ErbB2, CAM, CD31, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemo-protective, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, ER, ER-negative, ER-positive, ERK1, G1, GBC-SD, HCT116, HeLa, Hep G2,Hep 3B and SK-Hep1, HIF, HT-29, hypoxia-induced drug resistance, IGF-1, IL-1, iNOS, LM8, Lung cancer, MCF-7, MCP-1, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, neuro-protective, Osteosarcoma, p-Akt, p27, p53, PARP, PGE2, PI3K, PI3K/Akt, Pro-apoptotic, pro-oxidative, ROS, Sarcoma, T47D, MDA-MB-231, TNF, TRAIL, VEGF, VEGF, VEGFR

Wogonin

Cancer:
Breast, lung (NSCLC), gallbladder carcinoma, osteosarcoma, colon, cervical

Action: Neuro-protective, anti-lymphangiogenesis, anti-angiogenic, anti-estrogenic, chemo-sensitizer, pro-oxidative, hypoxia-induced drug resistance, anti-metastatic, anti-tumor, anti-inflammatory

Wogonin is a plant monoflavonoid isolated from Scutellaria rivularis (Benth.) and Scutellaria baicalensis (Georgi).

Breast Cancer; ER+ & ER-

Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell-cycle progression, and apoptosis. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by up-regulation of PARP and Caspase 3 cleavages as well as pro-apoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the down-regulation of the Akt-mediated canonical Wnt signaling pathway.

ER expression was down-regulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemo-preventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types (Chung et al., 2008).

Neurotransmitter Action

Kim et al. (2011) found that baicalein and wogonin activated the TREK-2 current by increasing the opening frequency (channel activity: from 0.05 ± 0.01 to 0.17 ± 0.06 in baicalein treatment and from 0.03 ± 0.01 to 0.29 ± 0.09 in wogonin treatment), while leaving the single-channel conductance and mean open time unchanged. Baicalein continuously activated TREK-2, whereas wogonin transiently activated TREK-2. Application of baicalein and wogonin activated TREK-2 in both cell attached and excised patches, suggesting that baicalein and wogonin may modulate TREK-2 either directly or indirectly with different mechanisms. These results suggest that baicalein- and wogonin-induced TREK-2 activation help set the resting membrane potential of cells exposed to pathological conditions and thus may give beneficial effects in neuroprotection.

Anti-metastasic

The migration and invasion assay was used to evaluate the anti-metastasis effect of wogonin. Wogonin at the dose of 1–10 µM, which did not induce apoptosis, significantly inhibited the mobility and invasion activity of human gallbladder carcinoma GBC-SD cells. In addition, the expressions of matrix metalloproteinase (MMP)-2, MMP-9 and phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) but not phosphorylated Akt were dramatically suppressed by wogonin in a concentration-dependent manner. Furthermore, the metastasis suppressor maspin was confirmed as the downstream target of wogonin.

These findings suggest that wogonin inhibits cell mobility and invasion by up-regulating the metastasis suppressor maspin. Together, these data provide novel insights into the chemo-protective effect of wogonin, a main active ingredient of Chinese medicine Scutellaria baicalensis (Dong et al., 2011).

Anti-tumor and Anti-metastatic

Kimura & Sumiyoshi (2012) examined the effects of wogonin isolated from Scutellaria baicalensis roots on tumor growth and metastasis using a highly metastatic model in osteosarcoma LM8-bearing mice. Wogonin (25 and 50mg/kg, twice daily) reduced tumor growth and metastasis to the lung, liver and kidney, angiogenesis (CD31-positive cells), lymphangiogenesis (LYVE-1-positive cells), and TAM (F4/80-positive cell) numbers in the tumors of LM8-bearing mice. Wogonin (10–100µM) also inhibited increases in IL-1β production and cyclooxygenase (COX)-2 expression induced by lipopolysaccharide in THP-1 macrophages. The anti-tumor and anti-metastatic actions of wogonin may be associated with the inhibition of VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation by the inhibition of COX-2 expression and IL-1β production in Tumor-associated macrophages (TAMs).

Anti-inflammatory

Wogonin extracted from Scutellariae baicalensis and S. barbata is a cell-permeable and orally available flavonoid that displays anti-inflammatory properties. Wogonin is reported to suppress the release of NO by iNOS, PGE2 by COX-2, pro-inflammatory cytokines, and MCP-1 gene expression and NF-kB activation (Chen et al., 2008).

Hypoxia-Induced Drug Resistance (MDR)

Hypoxia-induced drug resistance is a major obstacle in the development of effective cancer therapy. The reversal abilities of wogonin on   hypoxia resistance were examined and the underlying mechanisms discovered. MTT assay revealed that hypoxia increased maximal 1.71-, 2.08-, and 2.15-fold of IC50 toward paclitaxel, ADM, and DDP in human colon cancer cell lines HCT116, respectively. Furthermore, wogonin showed strong reversal potency in HCT116 cells in hypoxia and the RF reached 2.05. Hypoxia-inducible factor-1α (HIF-1α) can activate the expression of target genes involved in glycolysis. Wogonin decreased the expression of glycolysis-related proteins (HKII, PDHK1, LDHA), glucose uptake, and lactate generation in a dose-dependent manner.

In summary, wogonin could be a good candidate for the development of a new multi-drug resistance (MDR) reversal agent and its reversal mechanism probably is due to the suppression of HIF-1α expression via inhibiting PI3K/Akt signaling pathway (Wang et al., 2013).

NSCLC

Wogonin, a flavonoid originated from Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. In this study, the effect of a combination of TRAIL and wogonin was tested in a non-small-cell lung cancer xenografted tumor model in nude mice. Consistent with the in vitro study showing that wogonin sensitized A549 cells to TRAIL-induced apoptosis, wogonin greatly enhanced TRAIL-induced suppression of tumor growth, accompanied with increased apoptosis in tumor tissues as determined by TUNEL assay.

The down-regulation of these antiapoptotic proteins was likely mediated by proteasomal degradation that involved intracellular reactive oxygen species (ROS), because wogonin robustly induced ROS accumulation and ROS scavengers butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins in cells co-treated with wogonin and TRAIL.

These results show for the first time that wogonin enhances TRAIL's anti-tumor activity in vivo, suggesting this strategy has an application potential for clinical anti-cancer therapy (Yang et al., 2013).

Colon Cancer

Following treatment with baicalein or wogonin, several apoptotic events were observed, including DNA fragmentation, chromatin condensation and increased cell-cycle arrest in the G1 phase. Baicalein and wogonin decreased Bcl-2 expression, whereas the expression of Bax was increased in a dose-dependent manner compared with the control. Furthermore, the induction of apoptosis was accompanied by an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a dose-dependent manner.

The administration of baicalein to mice resulted in the inhibition of the growth of HT-29 xenografts without any toxicity following 5 weeks of treatment. The results indicated that baicalein induced apoptosis via Akt activation in a p53-dependent manner in the HT-29 colon cancer cells and that it may serve as a chemo-preventive or therapeutic agent for HT-29 colon cancer (Kim et al., 2012).

Breast

The involvement of insulin-like growth factor-1 (IGF-1) and estrogen receptor α (ERα) in the inhibitory effect of wogonin on the breast adenocarcinoma growth was determined. Moreover, the effect of wogonin on the angiogenesis of chick chorioallantoic membrane (CAM) was also investigated. The results showed wogonin and ICI182780 both exhibited a potent ability to blunt IGF-1-stimulated MCF-7 cell growth. Either of wogonin and ICI182780 significantly inhibited ERα and p-Akt expressions in IGF-1-treated cells. The inhibitory effect of wogonin showed no difference from that of ICI182780 on IGF-1-stimulated expressions of ERα and p-Akt. Meanwhile, wogonin at different concentrations showed significant inhibitory effect on CAM angiogenesis.

These results suggest the inhibitory effect of wogonin on breast adenocarcinoma growth via inhibiting IGF-1-mediated PI3K-Akt pathway and regulating ERα expression. Furthermore, wogonin has a strong anti-angiogenic effect on CAM model (Ma et al., 2012).

Chemoresistance; Cervical Cancer, NSCLC

Chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic. The combination of cisplatin with other agents has been recognized as a promising strategy to overcome cisplatin resistance. Previous studies have shown that wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid isolated from the root of the medicinal herb Scutellaria baicalensis Georgi, sensitizes cancer cells to chemotheraputics such as etoposide, adriamycin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TNF.

In this study, the non-small-cell lung cancer cell line A549 and the cervical cancer cell line HeLa were treated with wogonin or cisplatin individually or in combination. It was found for the first time that wogonin is able to sensitize cisplatin-induced apoptosis in both A549 cells and HeLa cells as indicated by the potentiation of activation of caspase-3, and cleavage of the caspase-3 substrate PARP in wogonin and cisplatin co-treated cells.

Results provided important new evidence supporting the potential use of wogonin as a cisplatin sensitizer for cancer therapy (He et al., 2012).

References

Chen LG, Hung LY, Tsai KW, et al. (2008). Wogonin, a bioactive flavonoid in herbal tea, inhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells. Mol Nutr Food Res. 52:1349-1357.


Chung H, Jung YM, Shin DH, et al. (2008). Anti-cancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts. Int J Cancer, 122(4):816-22.


Dong P, Zhang Y, Gu J, et al. (2011). Wogonin, an active ingredient of Chinese herb medicine Scutellaria baicalensis, inhibits the mobility and invasion of human gallbladder carcinoma GBC-SD cells by inducing the expression of maspin. J Ethnopharmacol, 137(3):1373-80. doi: 10.1016/j.jep.2011.08.005.


He F, Wang Q, Zheng XL, et al. (2012). Wogonin potentiates cisplatin-induced cancer cell apoptosis through accumulation of intracellular reactive oxygen species. Oncology Reports, 28(2), 601-605. doi: 10.3892/or.2012.1841.


Kim EJ, Kang D, Han J. (2011). Baicalein and wogonin are activators of rat TREK-2 two-pore domain K+ channel. Acta Physiologica, 202(2):185–192. doi: 10.1111/j.1748-1716.2011.02263.x.


Kim SJ, Kim HJ, Kim HR, et al. (2012). Anti-tumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Mol Med Rep, 6(6):1443-9. doi: 10.3892/mmr.2012.1085.


Kimura Y & Sumiyoshi M. (2012). Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis. Phytomedicine, 20(3-4):328-336. doi:10.1016/j.phymed.2012.10.016


Ma X, Xie KP, Shang F, et al. (2012). Wogonin inhibits IGF-1-stimulated cell growth and estrogen receptor α expression in breast adenocarcinoma cell and angiogenesis of chick chorioallantoic membrane. Sheng Li Xue Bao, 64(2):207-12.


Wang H, Zhao L, Zhu LT, et al. (2013). Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via down-regulation of HIF-1α and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. doi: 10.1002/mc.22052.


Yang L, Wang Q, Li D, et al. (2013). Wogonin enhances anti-tumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated down-regulation of cFLIPL and IAP proteins. Apoptosis, 18(5):618-26. doi: 10.1007/s10495-013-0808-8.

angiogenesis, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, AR, Chapter 7 Isolates and Cancer Research, Chemoprevention, inflammation, Prostate cancer

Wedelia Chinensis Extract: indole-3-carboxylaldehyde, wedelolactone, luteolin, apigenin

Cancer: Prostate

Action: Anti-inflammatory

Wedelia chinensis [(Osbeck) Merr.], also known as Chinese Wedelia, is widespread throughout China, India, Indochina, Indonesia, Philippines, Japan and Malaysia.

Prostate Cancer; AR Negative

The in vivo efficacy and mechanisms of action of oral administration of a standardized extract of W. chinensis were analyzed in animals bearing a subcutaneous or orthotopic prostate cancer xenograft. Exposure of prostate cancer cells to W. chinensis extract induced apoptosis selectively in androgen receptor (AR)-positive prostate cancer cells and shifted the proportion in each phase of cell-cycle toward G(2)-M phase in AR-negative prostate cancer cells. Oral herbal extract (4 or 40 mg/kg/d for 24–28 days) attenuated the growth of prostate tumors in nude mice implanted at both subcutaneous (31% and 44%, respectively) and orthotopic (49% and 49%, respectively) sites. The tumor suppression effects were associated with increased apoptosis and lower proliferation in tumor cells as well as reduced tumor angiogenesis. The anti-tumor effect of W. chinensis extract was correlated with accumulation of the principal active compounds, wedelolactone, luteolin, and apigenin, in vivo.

Anti-cancer action of W. chinensis extract was due to three active compounds that inhibit the AR signaling pathway. Oral administration of W. chinensis extract impeded prostate cancer tumorigenesis. Future studies of W. chinensis for chemoprevention or complementary medicine against prostate cancer in humans are thus warranted (Tsai et al., 2009).

Prostate Cancer; AR Positive

Reduction of inflammation is an important anti-cancer therapeutic opportunity, and chronic inflammation can augment tumor development in various types of cancers, including prostate cancer (PCa). Four anti-proliferative phytocompounds in Wedelia chinensis have been identified through their ability to modulate the androgen receptor (AR) activation of transcription from prostate-specific antigen promoter in PCa cells. The 50% inhibition concentration values of indole-3-carboxylaldehyde, wedelolactone, luteolin and apigenin, were 34.9, 0.2, 2.4 and 9.8 muM, respectively.

A formula that combined the phytocompounds in the same proportions as in the herbal extract decreased the dosage of each compound required to achieve maximal AR inhibition. In correlation with the AR suppression effect, these active compounds specifically inhibited the growth of AR-dependent PCa cells and as a combination formula they also synergistically suppressed growth in AR-dependent PCa cells. Our study has identified synergistic effects of active compounds in W. chinensis and demonstrated their potential in PCa prevention and therapy (Lin et al., 2007).

References

Lin FM, Chen LR, Lin EH, et al. (2007). Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells. Carcinogenesis, 28(12):2521-9.


Tsai CH, Lin FM, Yang YC, et al. (2009). Herbal extract of Wedelia chinensis attenuates androgen receptor activity and orthotopic growth of prostate cancer in nude mice. Clin Cancer Res, 15(17):5435-44.

3LL Lewis, anti-proliferative, anti-tumor, anti-tumor immunity, apoptosis, apoptosis-inducing, Breast cancer, Cervical cancer, Chapter 7 Isolates and Cancer Research, Choriocarcinoma, cytotoxic, Demethylation, G1, HeLa, CaSki, Immune, induces apoptosis, K562, Lung cancer, Lymphoma, MCF-7, MDA-MB-231

Trichosanthin (TCS)

Cancer:
Lung, leukemia, cervical, breast, leukemia/lymphoma, choriocarcinoma

Action: Demethylation, anti-tumor immunity, induces apoptosis

Breast

The 27-kDa trichosanthin (TCS) is a ribosome inactivating protein purified from tubers of the Chinese herbal plant Trichosanthes kirilowii Maximowicz (tian hua fen). Fang et al. (2012) extended the potential medicinal applications of TCS from HIV, ferticide, hydatidiform moles, invasive moles, to breast cancer. They found that TCS manifested anti-proliferative and apoptosis-inducing activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cells.

Leukemia/Lymphoma, Cervical Cancer, Choriocarcinoma

Trichosanthin (TCS) as a midterm abortifacient medicine has been used clinically in traditional Chinese medicine for centuries. Additionally, TCS manifests a host of pharmacological properties, for instance, anti-HIV and anti-tumor activities. TCS has been reported to inhibit cell growth of a diversity of cancers, including cervical cancer, choriocarcinoma, and leukemia/lymphoma, etc. Sha et al. (2013) reviewed the various anti-tumor activities of TCS and the mechanism of apoptosis it induced in these tumor cells.

Lung, Anti-tumor Immunity

In this study, Cai et al. (2011) focused on the effect of TCS on murine anti-tumor immune response in the 3LL Lewis lung carcinoma tumor model and explored the possible molecular pathways involved. In addition to inhibiting cell proliferation and inducing apoptosis in the 3LL tumor, TCS retarded tumor growth and prolonged mouse survival more significantly in C57BL/6 immunocompetent mice than in nude mice. Data demonstrate that TCS not only affects tumor cells directly, but also enhances anti-tumor immunity via the interaction between TSLC1 and CRTAM.

Induce Apoptosis

Over the past 20 years, TCS has been the subject of much research because of its potential anti-tumor activities. Many reports have revealed that TCS is cytotoxic in a variety of tumor cell lines in vitro and in vivo. Monoclonal antibody-conjugated TCS could enhance its anti-tumor efficacy; thus, TCS is considered to be a potential biological agent for cancer treatment. TCS is able to inhibit protein synthesis and consequently induce necrosis. Recent studies have demonstrated that TCS does indeed induce apoptosis in several tumor cell lines (Li et al., 2010).

Leukemia

Cultured human leukemia K562 cells treated with trichosanthin were examined. Analysis of the cells by single laser flow cytometry showed the sub-G1 peak. DNA extracted from these cells formed a characteristic 'ladder' on agarose gel electrophoresis. Under electromicroscope, typical morphological changes of apoptosis were also observed. From all of these findings, Kang et al. (1998) concluded that trichosanthin was able to induce apoptosis in K562 cells.

Cervical Cancer, Demethylation Activity

Epigenetic silencing of tumor suppressor genes is a well-established oncogenic process and the reactivation of tumor suppressor genes that have been silenced by promoter methylation is an attractive molecular target for cancer therapy. In this study, Huang et al. (2012) investigated the demethylation activity of trichosanthin and its possible mechanism of action in cervical cancer cell lines. HeLa human cervical adenocarcinoma and CaSki human cervical squamous carcinoma cells were treated with various concentrations (0, 20, 40 and 80 µg/ml) of TCS for 48 hours and the mRNA and protein expression levels of the tumor suppressor genes adenomatous polyposis coli (APC) and tumor suppressor in lung cancer 1 (TSLC1) were detected using reverse transcription (RT)-PCR and Western blotting, respectively.

TCS induced demethylation in HeLa and CaSki cells and this demethylation activity was accompanied by the decreased expression of DNMT1 and reduced DNMT1 enzyme activity. Results demonstrate for the first time that TCS is capable of restoring the expression of methylation-silenced tumor suppressor genes and is potentially useful as a demethylation agent for the clinical treatment of human cervical cancer.

References:

Cai YC, Xiong SD, Zheng YJ, et al. (2011). Trichosanthin enhances anti-tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM. Cellular & Molecular Immunology, (2011)8:359–367. doi:10.1038/cmi.2011.12.


Fang EF, Zhang CZ, Zhang L, et al. (2012). Trichosanthin inhibits breast cancer cell proliferation in both cell lines and nude mice by promotion of apoptosis. PLoS One, 7(9):e41592. doi: 10.1371/journal.pone.0041592.


Huang Y, Song H, Hu H, et al. (2012). Trichosanthin inhibits DNA methyltransferase and restores methylation-silenced gene expression in human cervical cancer cells. Mol Med Rep, 6(4):872-8. doi: 10.3892/mmr.2012.994.


Kong M, Ke YB, Zhou MY, et al. (1998). Study on Trichosanthin induced apoptosis of leukemia K562 cells. Shi Yan Sheng Wu Xue Bao, 31(3):233-43.


Li M, Li X, Li JC. (2010). Possible mechanisms of trichosanthin-induced apoptosis of tumor cells. Anat Rec (Hoboken), 293(6):986-92. doi: 10.1002/ar.21142.


Sha O, Niu J, Ng TB, et al. (2013). Anti-tumor action of trichosanthin, a type 1 ribosome-inactivating protein, employed in traditional Chinese medicine: a mini review. Cancer Chemother Pharmacol, 71(6):1387-93. doi: 10.1007/s00280-013-2096-y.

4T1, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, Autophagy, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, CT-26, cytotoxic, ERK, G1, growth-inhibitory, immunomodulating, Immunosuppressive activity, induces apoptosis, K562, MCF-7, MCF-7/TAM, MDR, MDR-1, MDR-1, Multi-Drug Resistance, Multi-drug resistance, neuro-protective, Oral cancer, P-gp, p21, p27, PR, S, SAS, tamoxifen resistance, TICs, VEGF, VEGF

Tetrandrine

Cancer:
Breast, leukemia, Oral cancer, renal cell carcinoma, colon

Action: Anti-inflammatory, tamoxifen resistance, cell-cycle arrest, anti-metastatic, MDR

Tetrandrine, a bisbenzylisoquinoline alkaloid from the root of Stephania tetrandra (S, Moore), exhibits a broad range of pharmacological activities, including immunomodulating, anti-hepatofibrogenetic, anti-inflammatory, anti-arrhythmic, anti-portal hypertension, anti-cancer and neuro-protective activities (Li, Wang, & Lu, 2001; Ji, 2011). Tetrandrine has anti-inflammatory and anti-fibrogenic actions, which make tetrandrine and related compounds potentially useful in the treatment of lung silicosis, liver cirrhosis, and rheumatoid arthritis (Kwan & Achike, 2002).

Tetrandrine generally presents its anti-cancer effects in micromolar concentrations. Tetrandrine induces different phases of cell-cycle arrest, depends on cancer cell types (Kuo & Lin, 2003; Meng et al., 2004; Ng et al., 2006) and also induces apoptosis in many human cancer cells, including leukemia, bladder, colon, hepatoma, and lung (Lai et al., 1998; Ng et al., 2006; Wu et al., 2010; He et al., 2011).

In vivo experiments have also demonstrated the potential value of tetrandrine against cancer activity. For example, the survival of mice subcutaneously inoculated with CT-26 cells is extended after daily oral gavage of 50 mg/kg or 150  mg/kg of tetrandrine (Wu et al., 2010). Tetrandrine also inhibits the expression of VEGF in glioma cells, has cytotoxic effect on ECV304 human umbilical vein endothelial cells, and suppresses in vivo angiogenesis (Chen et al., 2009). Tetrandrine-treated mice (10  mg/kg/day) have fewer metastases than vehicle-treated mice, and no acute toxicity or obvious changes can be observed in the body weight of both groups (Chang et al., 2004).

Leukemia

Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and chronic myeloid leukemia. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210Bcr-Abl mRNA and β-catenin protein (Xu et al., 2012).

Comparative in vitro studies show that tetrandrine has significantly greater suppressive effects on adherence, locomotion and 3H-deoxyglucose uptake of neutrophils, as well as the mitogen-induced lymphocyte responses and mixed lymphocyte reactions. By contrast, berbamine demonstrated a significantly greater capacity for inhibition of NK cell cytotoxicity. These results show that tetrandrine is superior to berbamine in most aspects of anti-inflammatory and immunosuppressive activity.

Since these two alkaloids differ by only one substitution in the side chain of one of the benzene rings, these findings may provide further insight into structure-activity relationships and clues to the synthesis and development of active analogues of this promising class of drugs for the treatment of chronic inflammatory diseases (Li et al., 1989).

MDR, Breast Cancer

Tetrandrine also has been found to have extensive pharmacological activity, including positive ion channel blockade and inhibition of multiple drug resistance proteins. These activities are very similar to that of salinomycin, a known drug targeting breast cancer initiation cells (TICs). Tetrandrine has been probed for this activity, targeting of breast cancer TICs. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a non-inflammatory metaplastic breast cancer cell line, were used in these studies.

In summary, tetrandrine demonstrates significant efficacy against in vitro surrogates for inflammatory and aggressive breast cancer TICs (Xu et al., 2011).

Leukemia, MDR

The potential mechanism of the chemotherapy resistance in acute myeloid leukemia (AML) is the multi-drug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from acute myeloid leukemia. In a multi-center clinical trial, 38 patients with poor risk forms of AML were treated with tetrandrine (TET), a potent inhibitor of the MDR-1 efflux pump, combined with daunorubicin (DNR), etoposide and cytarabine (TET–DEC). Overall, postchemotherapy marrow hypoplasia was achieved in 36 patients. Sixteen patients (42%) achieved complete remission or restored chronic phase, 9 achieved partial remission (PR) and 13 failed therapy.

These data indicate that TET–DEC was relatively well tolerated in these patients with poor risk AML, and had encouraging anti-leukemic effects (Xu et al., 2006).

Tamoxifen

Tetrandrine (Tet) had a significant reversal of tamoxifen drug resistance breast cancer cells resistant (MCF-7/TAM). The non-cytotoxic dose (0. 625 microg/mL) reversed the resistance by 2.0 folds. MRP1 was reduced at gene (P <0.05) and protein levels when Tet effected on MCF-7ITAM cells. Tet could reverse the drug resistance of MCF-7/TAM cells, and the reverse mechanism may be related to down-regulating MRP1 expression (Chen & Chen, 2013).

Colon Cancer

Tetrandrine (TET) exhibits anti-colon cancer activity. Gao et al. (2013) compared TET with chemotherapy drug doxorubicin in 4T1 tumor-bearing BALB/c mice model and found that TET exhibits anti-cancer metastatic and anti-angiogenic activities better than those of doxorubicin. Local blood perfusion of tumor was markedly decreased by TET after 3 weeks.

Mechanistically, TET treatment leads to a decrease in p-ERK level and an increase in NF- κ B levels in HUVECs. TET also regulated metastatic and angiogenic related proteins, including vascular endothelial growth factor, hypoxia-inducible factor-1 α, integrin β 5, endothelial cell specific molecule-1, and intercellular adhesion molecule-1 in vivo (Chen & Chen, 2013).

Tetrandrine significantly decreased the viability of SAS human oral cancer cells in a concentration- and time-dependent manner. Tet induced nuclear condensation, demonstrated by DAPI staining, and induces apoptosis and autophagy of SAS human cancer cells via caspase-dependent and LC3-I and LC3-II “American Typewriter”; “American Typewriter”;‑dependent pathways (Huang et al., 2013).

Renal Cancer

Tetrandrine treatment showed growth-inhibitory effects on human renal cell carcinoma (RCC) in a time- and dose-dependent manner. Additionally, flow cytometric studies revealed that tetrandrine was capable of inducing G1 cell-cycle arrest and apoptosis in RCC cells. Tet triggered apoptosis and cell-cycle arrest in RCC 786-O, 769-P and ACHN cells in vitro; these events are associated with caspase cascade activation and up-regulation of p21 and p27 (Chen, Ji, & Chen, 2013).

References

Chang KH, Liao HF, Chang HH, et al. (2004). Inhibitory effect of tetrandrine on pulmonary metastases in CT26 colorectal adenocarcinoma-bearing BALB/c mice. American Journal of Chinese Medicine, 32(6):863–872.


Chen HY, Chen XY. (2013). Tetrandrine reversed the resistance of tamoxifen in human breast cancer MCF-7/TAM cells: an experimental research. Zhongguo Zhong Xi Yi Jie He Za Zhi, 33(4):488-91.


Chen T, Ji B, Chen Y. (2013). Tetrandrine triggers apoptosis and cell-cycle arrest in human renal cell carcinoma cells. J Nat Med.


Chen Y, Chen JC, Tseng SH. (2009). Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. International Journal of Cancer, 124(10):2260–2269.


Gao JL, Ji X, He TC, et al. (2013). Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor-bearing Mice. Evid Based Complement Alternat Med, 2013:265061. doi: 10.1155/2013/265061.


He BC, Gao JL, Zhang BQ, et al. (2011). Tetrandrine inhibits Wnt/beta-catenin signaling and suppresses tumor growth of human colorectal cancer. Molecular Pharmacology, 79(2):211–219.


Huang AC, Lien JC, Lin MW, et al. (2013). Tetrandrine induces cell death in SAS human oral cancer cells through caspase activation-dependent apoptosis and LC3-I and LC3-II activation-dependent autophagy. Int J Oncol, 43(2):485-94. doi: 10.3892/ijo.2013.1952.


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


Kwan CY, Achike FI. (2002). Tetrandrine and related bis-benzylisoquinoline alkaloids from medicinal herbs: cardiovascular effects and mechanisms of action. Acta Pharmacol Sin, 23(12):1057-68.


Kuo PL and Lin CC. (2003). Tetrandrine-induced cell-cycle arrest and apoptosis in Hep G2 cells. Life Sciences, 73(2):243–252.


Lai YL, Chen YJ, Wu TY, et al. (1998). Induction of apoptosis in human leukemic U937 cells by tetrandrine. Anti-Cancer Drugs, 9(1):77–81.


Li SY, Ling LH, The BS, Seow WK and Thong YH. (1989). Anti-inflammatory and immunosuppressive properties of the bis-benzylisoquinolines: In vitro comparisons of tetrandrine and berbamine. International Journal of Immunopharmacology, 11(4):395-401 doi:10.1016/0192-0561(89)90086-6.


Meng LH, Zhang H, Hayward L, et al. (2004). Tetrandrine induces early G1 arrest in human colon carcinoma cells by down-regulating the activity and inducing the degradation of G 1-S-specific cyclin-dependent kinases and by inducing p53 and p21Cip1. Cancer Research, 64(24):9086–9092.


Ng LT, Chiang LC, Lin YT, and C. C. Lin CC. (2006). Anti-proliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. American Journal of Chinese Medicine, 34(1):125–135.


Wu JM, Chen Y, Chen JC, Lin TY, Tseng SH. (2010). Tetrandrine induces apoptosis and growth suppression of colon cancer cells in mice. Cancer Letters, 287(2):187–195.


Xu WL, Shen HL, Ao ZF, et al. (2006). Combination of tetrandrine as a potential-reversing agent with daunorubicin, etoposide and cytarabine for the treatment of refractory and relapsed acute myelogenous leukemia. Leukemia Research, 30(4):407-413.


Xu W, Debeb BG, Lacerda L, Li J, Woodward WA. (2011). Tetrandrine, a Compound Common in Chinese Traditional Medicine, Preferentially Kills Breast Cancer Tumor Initiating Cells (TICs) In Vitro. Cancers, 3:2274-2285; doi:10.3390/cancers3022274.


Xu XH, Gan YC, Xu GB, et al. (2012). Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/ β-catenin axis. Journal of Zhejiang University SCIENCE B, 13(11):867-874.

Anti-cancer, anti-tumor, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer

Taxus Cuspidata

Cancer: Leukemia, stomach, liver cervical

Action: Anti-cancer, chemo-sensitizer, anti-tumor

Taxus cuspidata (Siebold & Zucc.) is an evergreen, native to Japan, Korea, northeast China, and southeast Russia. Ten known taxoids, paclitaxel, 7-epi-taxol, taxol C, baccatin VI, taxayuntin C, taxuyunnanine C and its analogues (2-5), and yunnanxane (6), and an abietane, taxamairin A, were produced in the callus culture of Taxus cuspidata cultivated on a modified Gamborg's B5 medium in the presence of 0.5 mg/L NAA (Bai et al., 2004).

Anti-cancer, Chemo-sensitizer

Botanical medicines are increasingly combined with chemotherapeutics as anti-cancer drug cocktails. This study aimed to assess the chemotherapeutic potential of an extract of Taxus cuspidata (TC) needles and twigs produced by artificial cuttage and its co-effects as a cocktail with 5-fluorouracil (5-FU). TC extract reached inhibition rates of 70–90% in different human cancer cell lines but only 5–7% in normal mouse T/B lymphocytes, demonstrating broad-spectrum anti-cancer activity and low toxicity to normal cells of TC extract in vitro. TC extract inhibited cancer cell growth by inducing apoptosis and G(2)/M cell-cycle arrest. Most interestingly, TC extract and 5-FU, combined as a cocktail, synergistically inhibited the growth of cancer cells in vitro, with Combination Index values (CI) ranging from 0.90 to 0.26 at different effect levels from IC50 to IC90 in MCF-7 cells, CI ranging from 0.93 to 0.13 for IC40 to IC90 in PC-3M-1E8 cells, and CI < 1 in A549 cells.

In addition, the cocktail had lower cytotoxicity in normal human cell (HEL) than 5-FU used alone. Furthermore, TC extract did not affect the pharmacokinetics of 5-FU in rats. The combinational use of the Taxus Cuspidata (TC) extract with 5-FU displays strong cytotoxic synergy in cancer cells and low cytotoxicity in normal cells (Shang et al., 2011).

Anti-tumor Effects

Hydrophilic paclitaxel derivatives, as opposed to paclitaxel itself, can be detected by high pressure liquid chromatography in water decoctions from Taxus cuspidata. Jiang et al. (2010) hypothesize that water decoctions from T. cuspidata leaves exhibit anti-tumor effects in vivo, which may be aided by the activation of specific host mechanisms (e.g. stimulation of anti-tumor immunity) which are not present in vitro.

References

Bai, J., Kitabatake, M., Toyoizumi, K., et al. (2004). Production of biologically active taxoids by a callus culture of Taxus cuspidata. J Nat Prod, 67(1):58-63.


Jiang, S., Zhang, Y., Zu, Y., Wang, Z., Fu, Y. (2010). Anti-tumor activities of extracts and compounds from water decoctions of Taxus cuspidata. Am J Chin Med, 38(6):1107-14.


Shang W, Qiao J, Gu C, et al. (2011). Anti-cancer activity of an extract from needles and twigs of Taxus cuspidata and its synergistic effect as a cocktail with 5-fluorouracil. BMC Complementary and Alternative Medicine, 11:123. doi:10.1186/1472-6882-11-123

anti-tumor, apoptosis, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, G0/G1, G1, p53, Rectal cancer, SW480, SW620, VEGF, VEGF

Sophoridine (See also oxymatrine,Matrine)

Cancer: Colorectal, lung

Action: Cell-cycle arrest

Cell-cycle Arrest

Matrine, sophoridine and oxymatrine are isolates from Sophora Flavescens (Aiton).

Sophoridine (SRI) inhibited the growth of SW620 cells significantly in a dose-and time-dependent manner, and morphological characteristics of apoptosis were observed with condensation of the nucleus, cytoplasmic bubbling, and DNA fragmentation. A DNA ladder pattern of inter-nucleosomal fragmentation was observed. Compared with that of the control group, the percentage of the G0/G1 phase and the S phase cells increased after treatment by SRI. Apoptosis was induced in SW620 cells and underwent G0/G1 arrest with exposure to SRI as evidenced by flow cytometry results. Sophoridine could induce the inhibition of cell growth by means of apoptosis in a dose-and time-dependent manner, and cellcycle arrest at G0/G1 (Liang et al., 2008).

Colorectal Cancer

The anti-proliferation of sophoridine (SRI) in human colorectal cells SW480 was detected by3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The pathology and ultrastructure of xenograft tumors treated with SRI were also observed. SRI significantly inhibited the growth of SW480 cells, and the administration of SRI significantly inhibited the growth of xenograft tumors without apparent toxicity. SRI's mechanism of action involved the induction of apoptosis.

These results suggest that SRI produces obvious anti-tumor effects in vitro and in vivo. It supports the viability of developing SRI as a novel therapeutic prodrug for colorectal cancer treatment, as well as providing a method for identifying new anti-tumor drugs in traditional Chinese medicine (Liang et al., 2012).

Sophoridine can inhibit the growth of transplanted solid tumor of human colon cancer SW480 cell line, the mechanism of which involves the inhibition of p53 and VEGF expression. The volume and weight of the tumor xenograft in sophoridine group decreased in comparison with those in the control group. Sophoridine treatment resulted in lowered expressions of p53 and VEGF at both the protein and mRNA levels in the tumor explants as compared with the control group, with a tumor inhibition rate of 34.07% in nude mice (Wang et al., 2010).

References

Liang L, Zhang XH, Wang XY, Chen Y, Deng HZ. (2008). Effect of sophoridine on proliferation and apoptosis of human colon adenocarcinoma cells (SW620). Zhong Guo Yao Li Xue Tong Bao, 24(6): 782-787.


Liang W, Wang XY, Zhang XH, et al. (2012). Sophoridine exerts an anti-colorectal carcinoma effect through apoptosis induction in vitro and in vivo. Life Sciences, 91(25–26):1295–1303


Wang QR, Li CH, Fu XQ, et al. (2010). Effects of sophoridine on the growth and expressions of p53 and vascular endothelial growth factor of transplanted solid tumor SW480 in nude mice. Nan Fang Yi Ke Da Xue Xue Bao, 30(7):1593-6.

Anti-cancer, anti-tumor, anti-tumor activity, apoptosis, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, G1, Prostate cancer, S, Scutellaria Anti-cancer

Scutellaria (See also apigenin, baicalein, baicalin, chrysin, scutellarein, wogonin, scutellarin, carthamidin, isocarthamidin, wogonin)

Cancer: General anti-cancer, colon, breast, glioma,

Action: Scutellaria Anti-cancer, cell-cycle arrest

Malignant Glioma, Breast Carcinoma and Prostate Cancer

The extracts and individual flavonoids inhibited the proliferation of malignant glioma and breast carcinoma cells without affecting primary or non-malignant cells. The flavonoids exhibited different mechanisms of anti-tumor activity as well as positive interactions. The anti-tumor mechanisms involved induction of apoptosis and cell-cycle arrest at G1/G2. Of the extracts tested, leaf extracts of S. angulosa, S. integrifolia, S. ocmulgee and S. scandens were found to have strong anti-cancer activity (Parajuli et al., 2009).

Anti-Cancer

Scutellaria is a traditional herbal remedy with potential anti-cancer activity. The anti-cancer mechanisms of thirteen Scutellaria species were examined, and their leaf, stem and root extracts analyzed for levels of common biologically active flavonoids: apigenin, baicalein, baicalin, chrysin, scutellarein, and wogonin. Malignant glioma, breast carcinoma and prostate cancer cells were used to determine tumor-specific effects of Scutellaria on cell proliferation, apoptosis and cell-cycle progression, via the MTT assay and flow cytometry-based apoptosis and Cell cycle analysis. The extracts and individual flavonoids inhibited the proliferation of malignant glioma and breast carcinoma cells without affecting primary or non-malignant cells. The flavonoids exhibited different mechanisms of anti-tumor activity as well as positive interactions.

The anti-tumor mechanisms involved induction of apoptosis and cell-cycle arrest at G1/G2. Of the extracts tested, leaf extracts of S. angulosa, S. integrifolia, S. ocmulgee and S. scandens were found to have strong anti-cancer activity. This study provides basis for further mechanistic and translational studies into adjuvant therapy of malignant tumors using Scutellaria leaf tissues (Parajuli et al., 2009).

Colon

Scutellaria barbata (SB) is a medicinal plant that contains flavonone compounds such as scutellarein, scutellarin, carthamidin, isocarthamidin, and wogonin. A functional proteomic approach was used to study the inhibitory effects of a chemically standardized extract from SB in human colon adrencarcinoma, LoVo. Results suggest that the chemically standardized extract from SB can induce cell death in the human colon cancer cell line. Goh, Lee, & Ong (2005) showed that the proposed platform provided a rapid approach to study the molecular mechanism because of the inhibitory effects of different doses of the botanical extracts on LoVo cell lines. This included a network of proteins involved in metabolism, regulation of the cell-cycle, and transcription-factor activity.

References

Goh D, Lee YH, Ong ES. (2005). Inhibitory effects of a chemically standardized extract from Scutellaria barbata in human colon cancer cell lines, LoVo. J Agric Food Chem, 53(21):8197-204.


Parajuli P, Joshee N, Rimando AM, Mittal S, Yadav AK. (2009). In vitro anti-tumor mechanisms of various Scutellaria extracts and constituent flavonoids. Planta Med, 75(1):41-8. doi: 10.1055/s-0028-1088364.

anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, apoptosis induction, Apoptotic, AR, BAX, Bcl-2, Bladder cancer, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, cytotoxic, EJ, T24, 5637, G2/M, growth-inhibitory, HCT-116, L1210, MDA-MB-231, Melanoma, MT-4, Pro-apoptotic, pro-oxidative, Prostate cancer, Rectal cancer, ROS, S, XIAP

Sanguinarine (See also chelerythrine)

Cancer:
Prostate, bladder, breast, colon, melanoma, leukemia

Action: Pro-oxidative, anti-inflammatory, apoptosis induction

AR+/AR- Prostate Cancer

Sanguinarine, a benzophenanthridine alkaloid derived from the bloodroot plant Sanguinaria canadensis (L.), has been shown to possess anti-microbial, anti-inflammatory, anti-cancer and anti-oxidant properties. It has been shown that sanguinarine possesses strong anti-proliferative and pro-apoptotic properties against human epidermoid carcinoma A431 cells and immortalized human HaCaT keratinocytes. Employing androgen-responsive human prostate carcinoma LNCaP cells and androgen-unresponsive human prostate carcinoma DU145 cells, the anti-proliferative properties of sanguinarine against prostate cancer were also examined.

The mechanism of the anti-proliferative effects of sanguinarine against prostate cancer were examined by determining the effect of sanguinarine on critical molecular events known to regulate the cell-cycle and the apoptotic machinery.

A highlight of this study was the fact that sanguinarine induced growth-inhibitory and anti-proliferative effects in human prostate carcinoma cells irrespective of their androgen status. To our knowledge, this is the first study showing the involvement of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery during cell-cycle arrest and apoptosis of prostate cancer cells by sanguinarine. These results suggest that sanguinarine may be developed as an agent for the management of prostate cancer (Adhami et al., 2004).

Breast Cancer

The effects of this compound were examined on reactive oxygen species (ROS) production and its association with apoptotic tumor cell death using a human breast carcinoma MDA-MB-231 cell line. Cytotoxicity was evaluated by trypan blue exclusion methods. Apoptosis was detected using DAPI staining, agarose gel electrophoresis and flow cytometer. The expression levels of proteins were determined by Western blot analyzes and caspase activities were measured using colorimetric assays.

These observations clearly indicate that ROS is involved in the early molecular events in the sanguinarine-induced apoptotic pathway. Data suggests that sanguinarine-induced ROS are key mediators of MMP collapse, which leads to the release of cytochrome c followed by caspase activation, culminating in apoptosis (Choi, Kim, Lee & Choi, 2008).

Leukemia

Sanguinarine, chelerythrine and chelidonine are isoquinoline alkaloids derived from the greater celandine. They possess a broad spectrum of pharmacological activities. It has been shown that their anti-tumor activity is mediated via different mechanisms, which can be promising targets for anti-cancer therapy.

This study focuses on the differential effects of these alkaloids upon cell viability, DNA damage, and nucleus integrity in mouse primary spleen and lymphocytic leukemic cells, L1210. Sanguinarine and chelerythrine produced a dose-dependent increase in DNA damage and cytotoxicity in both primary mouse spleen cells and L1210 cells. Chelidonine did not show a significant cytotoxicity or damage DNA in both cell types, but completely arrested growth of L1210 cells.

Data suggests that cytotoxic and DNA-damaging effects of chelerythrine and sanguinarine are more selective against mouse leukemic cells and primary mouse spleen cells, whereas chelidonine blocks proliferation of L1210 cells. The action of chelidonine on normal and tumor cells requires further investigation (Kaminsky, Lin, Filyak, & Stoika, 2008).

T-lymphoblastic Leukemia

Apoptogenic and DNA-damaging effects of chelidonine (CHE) and sanguinarine (SAN), two structurally related benzophenanthridine alkaloids isolated from Chelidonium majus, were compared. Both alkaloids induced apoptosis in human acute T-lymphoblastic leukemia MT-4 cells. Apoptosis induction by CHE and SAN in these cells were accompanied by caspase-9 and -3 activation and an increase in the pro-apoptotic Bax protein. An elevation in the percentage of MT-4 cells possessing caspase-3 in active form after their treatment with CHE or SAN was in parallel to a corresponding increase in the fraction of apoptotic cells.

The involvement of the mitochondria in apoptosis induction by both alkaloids was supported by cytochrome C elevation in cytosol, with an accompanying decrease in cytochrome C content in the mitochondrial fraction. At the same time, two alkaloids under study differed drastically in their cell-cycle phase-specific effects, since only CHE arrested MT-4 cells at the G2/M phase. It was previously demonstrated, that CHE, in contrast to SAN, does not interact directly with DNA. (Philchenkov, Kaminskyy, Zavelevich, & Stoika, 2008).

Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. This study found that sanguinarine and chelerythrine induced apoptosis in human CEM T-leukemia cells, accompanied by an early increase in cytosolic cytochrome C that precedes caspases-8, -9 and -3 processing. Effects of sanguinarine and chelerythrine on mitochondria were confirmed by clear changes in morphology (3h), however chelidonine did not affect mitochondrial integrity.

Sanguinarine and chelerythrine also caused marked DNA damage in cells after 1h, but a more significant increase in impaired cells occurred after 6h. Chelidonine induced intensive DNA damage in 15–20% cells after 24h. Results demonstrated that rapid cytochrome C release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8 (Kaminskyy, Kulachkovskyy & Stoika, 2008).

Colorectal Cancer

The effects of sanguinarine, a benzophenanthridine alkaloid, was examined on reactive oxygen species (ROS) production, and the association of these effects with apoptotic cell death, in a human colorectal cancer HCT-116 cell line. Sanguinarine generated ROS, followed by a decrease in mitochondrial membrane potential (MMP), activation of caspase-9 and -3, and down-regulation of anti-apoptotic proteins, such as Bcl2, XIAP and cIAP-1. Sanguinarine also promoted the activation of caspase-8 and truncation of Bid (tBid).

Observations clearly indicate that ROS, which are key mediators of Egr-1 activation and MMP collapse, are involved in the early molecular events in the sanguinarine-induced apoptotic pathway acting in HCT-116 cells (Han, Kim, Yoo, & Choi, 2013).

Bladder Cancer

Although the effects of sanguinarine, a benzophenanthridine alkaloid, on the inhibition of some kinds of cancer cell growth have been established, the underlying mechanisms are not completely understood. This study investigated possible mechanisms by which sanguinarine exerts its anti-cancer action in cultured human bladder cancer cell lines (T24, EJ, and 5637). Sanguinarine treatment resulted in concentration-response growth inhibition of the bladder cancer cells by inducing apoptosis.

Taken together, the data provide evidence that sanguinarine is a potent anti-cancer agent, which inhibits the growth of bladder cancer cells and induces their apoptosis through the generation of free radicals (Han et al., 2013).

Melanoma

Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Current study has found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Sanguinarine disrupted the mitochondrial transmembrane potential (ΔΨ m), released cytochrome C and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Thus, pre-treatment with the thiol anti-oxidants NAC and GSH abrogated the killing activity of sanguinarine. Collectively, data suggests that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress (Burgeiro, Bento, Gajate, Oliveira, & Mollinedo, 2013).

References

Adhami YM, Aziz MH, Reagan-Shaw SR, et al. (2004). Sanguinarine causes cell-cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery. Mol Cancer Ther, 3:933


Burgeiro A, Bento AC, Gajate C, Oliveira PJ, Mollinedo F. (2013). Rapid human melanoma cell death induced by sanguinarine through oxidative stress. European Journal of Pharmacology, 705(1-3), 109-18. doi: 10.1016/j.ejphar.2013.02.035.


Choi WY, Kim GY, Lee WH, Choi YH. (2008). Sanguinarine, a benzophenanthridine alkaloid, induces apoptosis in MDA-MB-231 human breast carcinoma cells through a reactive oxygen species-mediated mitochondrial pathway. Chemotherapy, 54(4), 279-87. doi: 10.1159/000149719.


Han MH, Kim GY, Yoo YH, Choi YH. (2013). Sanguinarine induces apoptosis in human colorectal cancer HCT-116 cells through ROS-mediated Egr-1 activation and mitochondrial dysfunction. Toxicology Letters, 220(2), 157-66. doi: 10.1016/j.toxlet.2013.04.020.


Han MH, Park C, Jin CY, et al. (2013). Apoptosis induction of human bladder cancer cells by sanguinarine through reactive oxygen species-mediated up-regulation of early growth response gene-1. PLoS One, 8(5), e63425. doi: 10.1371/journal.pone.0063425.


Kaminskyy V, Lin KW, Filyak Y, Stoika R. (2008). Differential effect of sanguinarine, chelerythrine and chelidonine on DNA damage and cell viability in primary mouse spleen cells and mouse leukemic cells. Cell Biology International, 32(2), 271-277.


Kaminskyy V, Kulachkovskyy O, Stoika R. (2008) A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. Toxicology Letters, 177(3), 168-81. doi: 10.1016/j.toxlet.2008.01.009.


Philchenkov A, Kaminskyy V, Zavelevich M, Stoika R. (2008). Apoptogenic activity of two benzophenanthridine alkaloids from Chelidonium majus L. does not correlate with their DNA-damaging effects. Toxicology In Vitro, 22(2), 287-95.

angiogenesis, Anti-angiogenic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Chapter 7 Isolates and Cancer Research, chemo-prevention, COX-2, COX-2 inhibitor, cytotoxic, Head and neck cancer, HIF, induces apoptosis, MAPK, MDR, metastasis, MMP9, Multi-Drug Resistance, Multi-drug resistance, Oral cancer, p38, p53, Pro-apoptotic, reduction of cardiotoxicity, ROS, Squamous cell carcinoma, TNF

Salvianolic acid-B / Salvinal

Cancer:
Head and neck squamous cell carcinoma, oral squamous cell carcinoma, glioma

Action: MDR, reduction of cardiotoxicity, COX-2 inhibitor, inflammatory-associated tumor development, anti-cancer

Salvia miltiorrhiza contains a variety of anti-tumor active ingredients, such as the water-soluble components, salvianolic acid A, salvianolic acid B, salvinal, and liposoluble constituents, tanshinone I, tanshinone IIA, dihydrotanshinone I, miltirone, cryptotanshinone, ailantholide, neo-tanshinlactone, and nitrogen-containing compounds. These anti-tumor active components play important roles in the different stages of tumor evolution, progression and metastasis (Zhang & Lu, 2010).

Anti-cancer/MDR

Aqueous extracts of Salvia miltiorrhizae Bunge have been extensively used in the treatment of cardiovascular disorders and cancer in Asia. Recently, a compound, 5-(3-hydroxypropyl)-7-methoxy-2-(3'-methoxy-4'-hydroxyphenyl)-3-benzo[b]furancarbaldehyde (salvinal), isolated from this plant showed inhibitory activity against tumor cell growth and induced apoptosis in human cancer cells. In the present study, we investigated the cytotoxic effect and mechanisms of action of salvinal in human cancer cell lines. Salvinal caused inhibition of cell growth (IC50 range, 4-17 microM) in a variety of human cancer cell lines.

In particular, salvinal exhibited similar inhibitory activity against parental KB, P-glycoprotein-overexpressing KB vin10 and KB taxol-50 cells, and multi-drug resistance-associated protein (MRP)-expressing etoposide-resistant KB 7D cells.

Taken together, our data demonstrate that salvinal inhibits tubulin polymerization, arrests cell-cycle at mitosis, and induces apoptosis. Notably, Salvinal is a poor substrate for transport by P-glycoprotein and MRP. Salvinal may be useful in the treatment of human cancers, particularly in patients with drug resistance (Chang et al., 2004).

Glioma

Salvianolic acid B (SalB) has been shown to exert anti-cancer effect in several cancer cell lines. SalB increased the phosphorylation of p38 MAPK and p53 in a dose-dependent manner. Moreover, blocking p38 activation by specific inhibitor SB203580 or p38 specific siRNA partly reversed the anti-proliferative and pro-apoptotic effects, and ROS production induced by SalB treatment.

These findings extended the anti-cancer effect of SalB in human glioma cell lines, and suggested that these inhibitory effects of SalB on U87 glioma cell growth might be associated with p38 activation mediated ROS generation. Thus, SalB might be concerned as an effective and safe natural anti-cancer agent for glioma prevention and treatment (Wang et al., 2013).

Reduced Cardiotoxicity

Clinical attempts to reduce the cardiotoxicity of arsenic trioxide (ATO) without compromising its anti-cancer activities remain an unresolved issue. In this study, Wang et al., (2013b) determined that Sal B can protect against ATO-induced cardiac toxicity in vivo and increase the toxicity of ATO toward cancer cells.

The combination treatment significantly enhanced the ATO-induced cytotoxicity and apoptosis of HepG2 cells and HeLa cells. Increases in apoptotic marker cleaved poly (ADP-ribose) polymerase and decreases in procaspase-3 expressions were observed through Western blot. Taken together, these observations indicate that the combination treatment of Sal B and ATO is potentially applicable for treating cancer with reduced cardiotoxic side effects.

Oral Cancer

Sal B has inhibitory effect on oral squamous cell carcinoma (OSCC) cell growth. The anti-tumor effect can be attributed to anti-angiogenic potential induced by a decreased expression of some key regulator genes of angiogenesis. Sal B may be a promising modality for treating oral squamous cell carcinoma.

Sal B induced growth inhibition in OSCC cell lines but had limited effects on premalignant cells. A total of 17 genes showed a greater than 3-fold change when comparing Sal B treated OSCC cells to the control. Among these genes, HIF-1α, TNFα and MMP9 are specifically inhibited; expression of THBS2 was up-regulated (Yang et al., 2011).

Head and Neck Cancer

Overexpression of cyclooxygenase-2 (COX-2) in oral mucosa has been associated with increased risk of head and neck squamous cell carcinoma (HNSCC). Celecoxib is a non-steroidal anti-inflammatory drug, which inhibits COX-2 but not COX-1. This selective COX-2 inhibitor holds promise as a cancer-preventive agent. Concerns about the cardiotoxicity of celecoxib limit its use in long-term chemo-prevention and therapy. Salvianolic acid B (Sal-B) is a leading bioactive component of Salvia miltiorrhiza Bge, which is used for treating neoplastic and chronic inflammatory diseases in China.

Tumor volumes in Sal-B treated group were significantly lower than those in celecoxib treated or untreated control groups (p < 0.05). Sal-B inhibited COX-2 expression in cultured HNSCC cells and in HNSCC cells isolated from tumor xenografts. Sal-B also caused dose-dependent inhibition of prostaglandin E(2) synthesis, either with or without lipopolysaccharide stimulation. Taking these results together, Sal-B shows promise as a COX-2 targeted anti-cancer agent for HNSCC prevention and treatment (Hao et al., 2009).

Inflammatory-associated tumor development

A half-dose of daily Sal-B (40 mg/kg/d) and celecoxib (2.5 mg/kg/d) significantly inhibited JHU-013 xenograft growth relative to mice treated with a full dose of Sal-B or celecoxib alone. The combination was associated with profound inhibition of COX-2 and enhanced induction of apoptosis. Taken together, these results strongly suggest that a combination of Sal-B, a multifunctional anti-cancer agent, with low-dose celecoxib holds potential as a new preventive strategy in targeting inflammatory-associated tumor development (Zhao et al., 2010).

Squamous Cell Carcinoma

The results showed that Sal B significantly decreased the squamous cell carcinoma (SCC) incidence from 64.7 (11/17) to 16.7% (3/18) (P=0.004); angiogenesis was inhibited in dysplasia and SCC (P<0.01), with a simultaneous decrease in the immunostaining of hypoxia-inducible factor 1alpha and vascular endothelium growth factor protein (P<0.05). The results suggested that Sal B had inhibitory effect against the malignant transformation of oral precancerous lesion and such inhibition may be related to the inhibition of angiogenesis (Zhou, Yang, & Ge, 2006).

References

Chang JY, Chang CY, Kuo CC, et al. (2004). Salvinal, a novel microtubule inhibitor isolated from Salvia miltiorrhizae Bunge (Danshen), with antimitotic activity in Multi-drug-sensitive and -resistant human tumor cells. Mol Pharmacol, 65(1):77-84.


Hao Y, Xie T, Korotcov A, et al. (2009). Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivo via cyclooxygenase-2 and apoptotic pathways. Int J Cancer, 124(9):2200-9. doi: 10.1002/ijc.24160.


Wang ZS, Luo P, Dai SH, et al., (2013a). Salvianolic acid B induces apoptosis in human glioma U87 cells through p38-mediated ROS generation. Cell Mol Neurobiol, 33(7):921-8. doi: 10.1007/s10571-013-9958-z.


Wang M, Sun G, Wu P, et al. (2013b). Salvianolic Acid B prevents arsenic trioxide-induced cardiotoxicity in vivo and enhances its anti-cancer activity in vitro. Evid Based Complement Alternat Med, 2013:759483. doi: 10.1155/2013/759483.


Yang Y, Ge PJ, Jiang L, Li FL, Zhum QY. (2011). Modulation of growth and angiogenic potential of oral squamous carcinoma cells in vitro using salvianolic acid B. BMC Complement Altern Med, 11:54. doi: 10.1186/1472-6882-11-54.


Zhang W, Lu Y. (2010). Advances in studies on anti-tumor activities of compounds in Salvia miltiorrhiza. Zhongguo Zhong Yao Za Zhi, 35(3):389-92.


Zhao Y, Hao Y, Ji H, Fang Y, et al. (2010). Combination effects of salvianolic acid B with low-dose celecoxib on inhibition of head and neck squamous cell carcinoma growth in vitro and in vivo. Cancer Prev Res (Phila), 3(6):787-96. doi: 10.1158/1940-6207.CAPR-09-0243.


Zhou ZT, Yang Y, Ge JP. (2006). The preventive effect of salvianolic acid B on malignant transformation of DMBA-induced oral premalignant lesion in hamsters. Carcinogenesis, 27(4):826-32.

Akt, AMPK, angiogenesis, Anti-angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, anti-metastasis, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, enhanced paclitaxel absorption, Glioblastoma, HO-1, HT-29, Lymphoma, MAPK, MDR, metastasis, P-gp, p21, p38, p53, PARP, Pro-apoptotic, Prostate cancer, ROS, S, VEGF, VEGF

RG3 (See also Ginsenosides)

Cancer: Glioblastoma, prostate, breast, colon

Action: Anti-angiogenesis, MDR, enhances chemotherapy, MDR, enhanced paclitaxel absorption, anti-metastatic

RG3 is a ginsenoside isolated from red ginseng (Panax ginseng (L.)), after being peeled, heated, and dried.

Angiosuppressive Activity

Aberrant angiogenesis is an essential step for the progression of solid tumors. Thus anti-angiogenic therapy is one of the most promising approaches to control tumor growth.

Rg3 was found to inhibit the proliferation of human umbilical vein endothelial cells (HUVEC) with an IC50 of 10 nM in Trypan blue exclusion assay.

Rg3 (1-10(3) nM) also dose-dependently suppressed the capillary tube formation of HUVEC on the Matrigel in the presence or absence of 20 ng/ml vascular endothelial growth factor (VEGF). The Matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, which play an important role in the degradation of basement membrane in angiogenesis and tumor metastasis present in the culture supernatant of Rg3-treated aortic ring culture were found to decrease in their gelatinolytic activities. Taken together, these data underpin the anti-tumor properties of Rg3 through its angiosuppressive activity (Yue et al., 2006).

Glioblastoma

Rg3 has been reported to exert anti-cancer activities through inhibition of angiogenesis and cell proliferation. The mechanisms of apoptosis by ginsenoside Rg3 were related with the MEK signaling pathway and reactive oxygen species. Our data suggest that ginsenoside Rg3 is a novel agent for the chemotherapy of glioblastoma multiforme (GBM) (Choi et al., 2013).

Sin, Kim, & Kim (2012) report that chronic treatment with Rg3 in a sub-lethal concentration induced senescence-like growth arrest in human glioma cells. Rg3-induced senescence was partially rescued when the p53/p21 pathway was inactivated. Data indicate that Rg3 induces senescence-like growth arrest in human glioma cancer through the Akt and p53/p21-dependent signaling pathways.

MDR/Enhanced Paclitaxel Absorption

The penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Rg3 also inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The relative bioavailability (RB)% of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumor activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05).

The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumor activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route (Yang et al., 2012).

Prostate Cancer

The anti-proliferation effect of Rg3 on prostate cancer cells has been well reported. Rg3 treatment triggered the activation of p38 MAPK; and SB202190, a specific inhibitor of p38 MAPK, antagonized the Rg3-induced regulation of AQP1 and cell migration, suggesting a crucial role for p38 in the regulation process. Rg3 effectively suppresses migration of PC-3M cells by down-regulating AQP1 expression through p38 MAPK pathway and some transcription factors acting on the AQP1 promoter (Pan et al., 2012).

Enhances Chemotherapy

The clinical use of cisplatin (cis-diamminedichloroplatinum II) has been limited by the frequent emergence of cisplatin-resistant cell populations and numerous other adverse effects. Therefore, new agents are required to improve the therapy and health of cancer patients. Oral administration of ginsenoside Rg3 significantly inhibited tumor growth and promoted the anti-neoplastic efficacy of cisplatin in mice inoculated with CT-26 colon cancer cells. In addition, Rg3 administration remarkably inhibited cisplatin-induced nephrotoxicity, hepatotoxicity and oxidative stress.

Rg3 promotes the efficacy of cisplatin by inhibiting HO-1 and NQO-1 expression in cancer cells and protects the kidney and liver against tissue damage by preventing cisplatin-induced intracellular ROS generation (Lee et al., 2012).

Colon Cancer

Rg3-induced apoptosis in HT-29 cells is mediated via the AMPK signaling pathway, and that 20(S)-Rg3 is capable of inducing apoptosis in colon cancer. Rg3-treated cells displayed several apoptotic features, including DNA fragmentation, proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) and morphological changes. 20(S)-Rg3 down-regulated the expression of anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl2), up-regulated the expression of pro-apoptotic protein of p53 and Bcl-2-associated X protein (Bax), and caused the release of mitochondrial cytochrome c, PARP, caspase-9 and caspase-3 (Yuan et al., 2010).

Anti-metastatic

Studies have linked Rg3 with anti-metastasis of cancer in vivo and in vitro and the CXC receptor 4 (CXCR4) is a vital molecule in migration and homing of cancer to the docking regions. At a dosage without obvious cytotoxicity, Rg3 treatment elicits a weak CXCR4 stain color, decreases the number of migrated cells in CXCL12-elicited chemotaxis and reduces the width of the scar in wound healing and Rg3 is a new CXCR4 inhibitor (Chen et al., 2011).

References

Chen XP, Qian LL, Jiang H, Chen JH. (2011). Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line. Int J Clin Oncol, 16(5):519-23. doi: 10.1007/s10147-011-0222-6.


Choi YJ, Lee HJ, Kang DW, et al. (2013). Ginsenoside Rg3 induces apoptosis in the U87MG human glioblastoma cell line through the MEK signaling pathway and reactive oxygen species. Oncol Rep. doi: 10.3892/or.2013.2555.


Lee CK, Park KK, Chung AS, Chung WY. (2012). Ginsenoside Rg3 enhances the chemosensitivity of tumors to cisplatin by reducing the basal level of nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1/NAD(P)H quinone oxidoreductase-1 and prevents normal tissue damage by scavenging cisplatin-induced intracellular reactive oxygen species. Food Chem Toxicol, 50(7):2565-74. doi: 10.1016/j.fct.2012.01.005.


Pan XY, Guo H, Han J, et al. (2012). Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells. Eur J Pharmacol, 683(1-3):27-34. doi: 10.1016/j.ejphar.2012.02.040.


Sin S, Kim SY, Kim SS. (2012). Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells. Int J Oncol., 41(5):1669-74. doi: 10.3892/ijo.2012.1604.


Yang LQ, Wang B, Gan H, et al. (2012). Enhanced oral bioavailability and anti-tumor effect of paclitaxel by 20(s)-ginsenoside Rg3 in vivo. Biopharm Drug Dispos., 33(8):425-36. doi: 10.1002/bdd.1806.


Yuan HD, Quan HY, Zhang Y, et al. (2010). 20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Mol Med Rep., 3(5):825-31. doi: 10.3892/mmr.2010.328.


Yue PY, Wong DY, Wu PK, et al. (2006). The angiosuppressive effects of 20 (R)-ginsenoside Rg3. Biochem Pharmacol, 72(4):437-45.

anti-tumor, anti-tumor activity, apoptosis, Breast cancer, Chapter 7 Isolates and Cancer Research, ER, ER-positive, Estrogen modulator

Psoralen and Bakuchiol

Cancer: Breast

Action: Estrogen modulator

The seed of Psoralea corylifolia L. (PCL), a well-known traditional Chinese medicine, has been applied as a tonic or an aphrodisiac agent and commonly used as a remedy for bone fracture, osteomalacia and osteoporosis in China (Lim et al., 2009).

Estrogen Modulator

The estrogen receptor subtype-selective activities of the extracts and compounds derived from PCL were analyzed using the HeLa cell assay. The different fractions, including petroleum ether, CH(2)Cl(2) and EtOAc fractions of the EtOH extract of PCL, showed significant activity in activating either ERalpha or ERbeta, whereas the n-BuOH fraction showed no estrogenic activity. Further chromatographic purification of the active fractions yielded seven compounds including the two coumarins isopsoralen and psoralen, the four flavonoids isobavachalcone, bavachin, corylifol A and neobavaisoflavone, and the meroterpene phenol, bakuchiol. In reporter gene assay, the two coumarins (10(-8)-10(-5)M) acted as ERalpha-selective agonists while the other compounds (10(-9)-10(-6)M) activated both ERalpha and ERbeta.

The estrogenic activities of all compounds could be completely suppressed by the pure estrogen antagonist, ICI 182,780, suggesting that the compounds exert their activities through ER. Only psoralen and isopsoralen as ERalpha agonists promoted MCF-7 cell proliferation significantly. Although all the compounds have estrogenic activity, they may exert different biological effects. These data suggest that both ER subtype-selective and non-selective activities in compounds derived from PCL indicated that PCL could be a new source for selective estrogen-receptor modulators (Xin et al., 2010).

Breast Cancer

The in vitro anti-tumor activity of bakuchiol was examined, compared with tamoxifen. The result of biological activities showed that bakuchiol could inhibit human breast cancer and the IC50 values were 2.89 x 10(-5) mol L(-1) and 8.29 x 10(-3) mol L(-1) against the cells line T-47D and MDA-MB-231 respectively (Chen et al., 2010).

In vitro inhibitory effects of various concentrations of psoralen (25, 12. 5, 6. 25 and 3. 125 µg/mL respectively) on MCF-7 cells with estrogen-receptor (ER) positive and on MDA-MB-231 cells with ER negative were carried out. Psoralen had no inhibitory effect on the growth of MDA-MB-231 cells, but cell apoptosis was increased at early stage. There were 1,053 genes with differential expression in MCF-7 cells assessed by cDNA chips. Of the expression of 1,053 genes, the expression of 657 genes was down-regulated and that of 456 gene was up-regulated.

Psoralen has certain inhibitory effect on the proliferation of ER-positive MCF-7 cells, and its inhibitory mechanism on the growth of breast cancer is probably related to the arrest of the cell at G2 phase by the drug (Tan et al., 2009).

References

Chen HL, Feng HJ, Li YC. (2010). Vitro anti-tumor activity and synthesis of the key intermediate of bakuchiol. Yao Xue Xue Bao, 45(4):467-70.


Lim SH, Ha TY, Kim SR, et al. (2009). Ethanol extract of Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague-Dawley rats. Br J Nutr., 101(7):1031-1039


Tan M, Sun J, Zhao H, et al. (2009). Comparative Study on the Anti-tumor Effects of Psoralen on Human Breast Cancer Cell Line MCF-7 and MDA-MB-231 in Vitro. Guang Zhou Zhong Yi Yao Da Xue Xue Bao, 26(4): 359-362.


Xin D, Wang H, Yang J, et al. (2010). Phytoestrogens from Psoralea corylifolia reveal estrogen receptor-subtype selectivity. Phytomedicine, 17(2):126-31. doi: 10.1016/j.phymed.2009.05.015.

A549, LL/2, Akt, angiogenesis, Anti-cancer, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, c-Myc, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Cortex periplocae, Cytostatic, cytostatic effect, cytotoxic, ERK, G0/G1, G1, HeLa, K562, Lung cancer, MCF-7, PC3, Pro-apoptotic, QG-56, SMMC-7721, SW480, T24, TE-13, Eca-109, TRAIL, U937

Periplocin

Cancer: Lung, colorectal, leukemia

Action: Apoptosis-inducing, cytostatic effect

Apoptosis

The anti-tumor component of Cortex periplocae is periplocin. Periplocin is one of the cardenolides isolated from cortex periplocae which is used for treatment of rheumatoid arthritis and reinforcement of bones and tendons in traditional medicine.

Periplocin has been reported to inhibit many cell lines, including MCF-7, TE-13, QG-56, SMMC-7721, T24, Hela, K562, TE-13 and Eca-109 cells. Studies have shown that periplocin reduces the expression of survivin, an inhibitor of apoptosis. It also releases caspases-3 and -7 from complexes and thereby increases their activities, ultimately inducing tumor cell apoptosis (Zhao et al., 2009).

Lung Cancer

The anti-tumor activity of periplocin was investigated in lung cancer cells both in vitro and in vivo, and its anti-cancer mechanism was explored. Periplocin inhibited the growth of lung cancer cells and induced their apoptosis in a time- and dose-dependent manner by cell-cycle arrest in G0/G1 phase. Periplocin exhibited anti-tumor activity both in human (A549) and mouse (LL/2) lung cancer xenograft models. Immunohistochemical analysis revealed that intratumoral angiogenesis was significantly suppressed.

Furthermore, anti-cancer activity mediated by periplocin was associated with decreased level of phosphorylated AKT and ERK both in vitro and in vivo, which are important for cell growth and survival. Moreover, periplocin induced apoptosis by down-regulating Bcl-2 and up-regulating Bax, leading to activation of caspase-3 and caspase-9.

These findings suggest that periplocin could inhibit the growth of lung cancer both in vitro and in vivo, which could be attributed to the inhibition of proliferation and the induction of apoptosis signaling pathways, such as AKT and ERK. These observations provide further evidence on the anti-tumor effect of periplocin, and it may be of importance to further explore its potential role as a therapeutic agent for cancer (Lu et al., 2010).

Colorectal Carcinomas

The Wnt/beta-catenin signaling pathway plays an important role in the development and progression of human cancers, especially in colorectal carcinomas. Periplocin extracted from cortex periplocae (CPP) significantly inhibited the proliferation of SW480 cells in a time-and dose-dependent manner (P<0.01). CPP (0.5 microg/mL) also caused G0/G1 cell-cycle arrest of SW480 cells and induced cell apoptosis (P<0.05). Compared to untreated control cells, after the treatment with CPP, the protein levels of beta-catenin in total cell lysates, cytosolic extracts, and nuclear extracts were reduced (P<0.01); the binding activity of the TCF complex in nucleus to its specific DNA binding site was suppressed; mRNAs of the downstream target genes survivin, c-myc and cyclin D1 were decreased (P<0.01) while beta-catenin mRNA remained unchanged.

CPP could significantly inhibit the proliferation of SW480 cells, which may be through down-regulating the Wnt/beta-catenin signaling pathway (Du et al., 2009).

Pro-apoptotic and Cytostatic Effect/Leukemia

Cardenoliddes are steroid glycosides which are known to exert cardiotonic effects by inhibiting the Na(+)/K(+)-ATPase. Several of these compounds have been shown also to possess anti-tumor potential. The aim of the present work was the characterization of the tumor cell growth inhibition activity of four cardenolides, isolated from Periploca graeca L., and the mechanisms underlying such an effect.

The pro-apoptotic and cytostatic effect of the compounds was tested in U937 (monocytic leukemia) and PC3 (prostate adenocarcinoma). Characterization of apoptosis and cell-cycle impairment was obtained by cytofluorimetry and WB. Periplocymarin and periplocin were the most active compounds, periplocymarin being more effective than the reference compound ouabain. The reduction of cell number by these two cardenolides was due in PC3 cells mainly to the activation of caspase-dependent apoptotic pathways, while in U937 cells to the induction of cell-cycle impairment without extensive cell death. Interestingly, periplocymarin, at cytostatic but non-cytotoxic doses, was shown to sensitize U937 cells to TRAIL. Taken together, these data outline that cardiac glycosides are promising anti-cancer drugs and contribute to the identification of new natural cardiac glycosides to obtain chemically modified non-cardioactive/low toxic derivatives with enhanced anti-cancer potency (Bloise et al., 2009).

References

Bloise E, Braca A, De Tommasi N, Belisario MA. (2009). Pro-apoptotic and cytostatic activity of naturally occurring cardenolides. Cancer Chemother Pharmacol, 64(4):793-802. doi: 10.1007/s00280-009-0929-5.


Du YY, Liu X, Shan BE. (2009). Periplocin extracted from cortex periplocae induces apoptosis of SW480 cells through inhibiting the Wnt/beta-catenin signaling pathway. Ai Zheng, 28(5):456-60.


Lu ZJ, Zhou Y, Song Q, et al. (2010). Periplocin inhibits growth of lung cancer in vitro and in vivo by blocking AKT/ERK signaling pathways. Cell Physiol Biochem, 26(4-5):609-18. doi: 10.1159/000322328.


Zhao LM, Ai J, Zhang Q, et al. (2009). Periplocin (a sort of ethanol from Cortex periplocae) induces apoptosis of esophageal carcinoma cells by influencing expression of related genes. Tumor (Chin), 29:1025-1030.

angiogenesis, Anti-angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, AP-1, apoptosis, Apoptotic, BAX, Bcl-2, bFGF, Breast cancer, c-Jun, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, chemotherapy support, Colon Cancer or Colorectal cancer, Cytostatic, cytotoxic, Diarrhea or Constipation, ERK, G0/G1, G1, G2/M, Hair Loss, IAP, IL-2, IL-8, immunotolerance, induces apoptosis, JNK, Liver cancer, Lung cancer, MNNG/HOS, Nausea and Vomiting, NFAT, PANC-1, Pancreatic cancer, radiation support, radiotherapy, RANK, Rectal cancer, Sarcoma, sIL-2R, tumor-inhibitory, VEGF, VEGF

Oxymatrine (Ku Shen)

Cancer:
Sarcoma, pancreatic, breast, liver, lung, oral, colorectal, stomach, gastric, adenoid cystic carcinoma

Action: Anti-angiogenesis, anti-inflammatory, anti-proliferative, chemo-sensitizer, chemotherapy support, cytostatic, radiation support, immunotolerance, induces apoptosis, decreases side-effects of Intensity Modulated Radiation Therapy (IMRT), Transcatheter Hepatic Arterial Chemoembolization (TACE)

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).

Angiogenesis

Oxymatrine has been found to inhibit angiogenesis when administered by injection. The tumor-inhibitory rate and the vascular density were tested in animal tumor model with experimental treatment. The expression of VEGF and bFGF were measured by immunistological methods. When high doses were 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).

Immunotolerance

Matrine, a small molecule derived from the root of Sophora flavescens AIT, was demonstrated to be effective in inducing T cell anergy in human Jurkat cells. Induction of immunotolerance has become a new strategy for treating autoimmune conditions in recent decades. However, so far there is no ideal therapeutics available for clinical use. Medicinal herbs are a promising potential source of immunotolerance inducers. Bioactive compounds derived from medicinal plants were screened for inducing T cell anergy in comparison with the effect of well-known T cell anergy inducer, ionomycin.

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, when the cells were stimulated by antigens, anti-OKT3 plus anti-CD28. Mechanistic study showed that ionomycin and matrine could up-regulate the anergy-associated gene expressions of CD98 and Jumonji and activate nuclear factor of activated T-cells (NFAT) nuclear translocation in absence of cooperation of AP-1 in Jurkat cells. 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).

Induces Apoptosis

The cytotoxic effects of oxymatrine on MNNG/HOS cells were examined by MTT and bromodeoxyuridine (BrdU) incorporation assays. The percentage of apoptotic cells and the level of mitochondrial membrane potential ( Δψ m) were assayed by flow cytometry. The levels of apoptosis-related proteins were measured by Western blot analysis or enzyme assay Kit.

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 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

Cell viability assay showed that treatment of PANC-1 pancreatic cancer cells with oxymatrine resulted in cell growth inhibition in a dose- and time-dependent manner. 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).

Induces Apoptosis in Pancreatic Cancer

Oxymatrine inhibited cell viability and induced apoptosis of PANC-1 cells in a time- and dose-dependent manner. This was accompanied by down-regulated expression of Livin and Survivin genes while the Bax/Bcl-2 ratio was up-regulated. 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).

Decreases Side-effects of Intensity Modulated Radiation Therapy (IMRT)

The levels of sIL-2R and IL-8 in peripheral blood cells of patients with rectal cancer were measured after treatment with the compound matrine, in combination with radiation. Eighty-four patients diagnosed with rectal carcinoma 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 effects and the levels of IL-8 and sIL-2R tested by ELISA pre-radiation and post-radiation were compared. In addition, 42 healthy people were singled out from the physical examination center in the People's Hospital of Yichun city, which were considered as healthy controls.

The clinical effect and survival rate in the therapeutic group was 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 progress.

The quality of life in the therapeutic group was higher than tthat in the control group, by rank sum test. SIL-2R and IL-8 examination found that serum levels of sIL-2R and IL-8 were higher in rectal cancer patients before treatments than those in the healthy groups, by student test.

However, sIL-2R and IL-8 serum levels were found significantly lower in the 84 rectal cancer patients after radiotherapy. 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. Side-effects of hepatotoxicity (11.9%) and radiation proctitis (9.52%) were fewer in the therapeutic group.

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

The clinical effect of matrine injection, combined with S-1 and cisplatin (SP), in the treatment of advanced gastric cancer was investigated. Seventy-six cases of advanced gastric cancer were 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. Therapeutic effect of the two groups of patients did not differ significantly. Occurrence rate of symptom indexes in the treatment group were lower than those of control group, with exception of nausea and vomiting, in which there was no significant difference.

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

The effects of compound radix Sophorae flavescentis injection on proliferation, apoptosis and Caspase-3 expression in human adenoid cystic carcinoma ACC-2 cells was investigated.

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). IC50 of ACC-2 was 0.84 g/ml. Flow cytometry indicated that radix Sophorae flavescentis injection could arrest ACC-2 cells at the G0/G1 phase, with a gradual decrease of presence in the G2/M period and S phase. With an increase in dosage, ACC-2 cell apoptosis rate increased significantly (P < 0.05 or 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 Post-operative Chemotherapy

A retrospective analysis of oncological data of 70 post-operative 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 to a cycle) were compared.

The objective remission rate of therapy group compared with that of control group was not statistically significant (P > 0.05), while the difference of the disease control rate in two groups was statistically significant (P < 0.05). 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 Effusions

The therapeutic efficiency of fufangkushen injection, 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 fufangkushen plus IL-2, fufangkushen plus α-tFN, and IL-2 plus α-IFN, respectively. The control group was divided into three groups and injected fufangkushen, IL-2 and α-IFN, respectively. Therapeutic efficiency and adverse reactions were observed after four weeks.

The effective rate of fufangkushen, IL-2, and α-IFN in a combination was significantly superior to single pharmacotherapy. The effective rate of fufangkushen plus ct-IFN was highest. In adverse reactions, the incidence of fever, chest pains, and the reaction of gastrointestinal tract in the treatment group were significantly less than in the matched group.

The effect of fufangkushen, IL-2, and α-IFN, in a combination, on lung cancer with pleural effusions was significantly better than single pharmacotherapy. Moreover, the effect of fufangknshen plus IL-2 or α-IFN had the greatest effect (Hu & Mei, 2012).

Colorectal Cancer Immunologic Function

The effects of compound Kushen (Radix sophorae flavescentis) injection on the immunologic function of patients after colorectal cancer resection, were studied.

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 mL·d-1 compound Kushen injection, for 10 days 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).

After chemotherapy, the numbers of CD3+,CD4+T cells, NK cells and CD4+/CD8+ ratio were higher in the experimental group than in the control group (P0.05), while the number of CD8+T lymphocyte was similar between two groups. Compound Kushen injection can improve the immunologic function of patients receiving chemotherapy after colorectal cancer resection (Chen, Yu, Yuan, & Yuan, 2009).

Stage III and IV non-small-cell lung cancer (NSCLC)

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 chemotherapy was performed for 4 cycles of 3 weeks, and the therapeutic efficacy was evaluated every 2 weeks. 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 serum lgA levels were not significantly different in the two groups.

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

Suppression effects of different concentrations of matrine injection and matrine injection combined with anti-tumor drugs on lung cancer cells were measured by methyl thiazolyl tetrazolium (MTT) colorimetric assay.

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).

Transcatheter Hepatic Arterial Chemoembolization (TACE)

The effect of composite Kushen injection combined with transcatheter hepatic arterial chemoembolization (TACE) on unresectable primary liver cancer, was studied.

Fifty-seven patients with unresectable primary liver cancer were randomly divided into two 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. The clinical curative effects were observed after treatment in both groups.

One-, 2-, and 3-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).

References

An AJ, An GW, Wu YC. (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 SJ, 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- κ B-mediated VEGF signaling pathway. Oncol Rep, 30(2):589-95. doi: 10.3892/or.2013.2529.


Fan CX, Lin CL, Liang L, et al. (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.


Hu DJ, Mei, XD. (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.


Kong QZ, Huang DS, 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.


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;2012:373219. doi: 10.1155/2012/373219.


Wang HM, Cheng XM. (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 WH, Sheng JW, Xia HM, et al. (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.


Zhu MY, Jiang ZH, Lu YW, Guo Y, Gan JJ. (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.

A549, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, Breast cancer, CDC2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, COX-2, G2/M, induces apoptosis, Lung cancer, MCF-7, p21, p53, Panc-28, Pancreatic cancer, PC3, Pro-apoptotic, pro-apoptotic with 5-FU, Prostate cancer, Radio-sensitizer, radio-sensitizing, ROS

Oleanolic Acid (OA)

Cancer:
Pancreatic, hepatocellular carcinoma, prostate, lung, gastric, breast

Action: Radio-sensitizer, pro-apoptotic with 5-FU

Oleanolic acid (OA), a pentacyclic triterpenoid isolated from several plants, including Rosa woodsii (Lindl.), Prosopis glandulosa (Torr.), Phoradendron juniperinum (Engelm. ex A. Gray), Syzygium claviflorum (Roxburgh), Hyptis capitata (Jacq.) and Ternstromia gymnanthera (L.) exhibits potential anti-tumor activity against many tumor cell lines. Mistletoe contains water-insoluble triterpenoids, mainly oleanolic acid, that have anti-tumorigenic effects (StrŸh et al., 2013).

Pancreatic Cancer

Results of a study by Wei et al. (2012) showed that the proliferation of Panc-28 cells was inhibited by OA in a concentration-dependent manner, with an IC50 (The half maximal inhibitory concentration) value of 46.35 µg ml−1. The study also showed that OA could induce remarkable apoptosis and revealed that OA could induce Reactive Oxygen Species (ROS) generation, mitochondrial depolarization, release of cytochrome C, lysosomal membrane permeabilization and leakage of cathepin B. Further study confirmed that ROS scavenger vitamin C could reverse the apoptosis induced by OA in Panc-28 cells.

These results provide evidence that OA arrests the cell-cycle and induces apoptosis, possibly via ROS-mediated mitochondrial and a lysosomal pathway in Panc-28 cell.

The effects of the combination of OA and 5-fluorouracil (5-FU) on Panc-28 human pancreatic cells showed that combined use synergistically potentiated cell death effects on these cells, and that the pro-apoptotic effects were also increased. The expression of apoptosis related proteins was also affected in cells treated with the combination of OA and 5-FU, including activation of caspases-3 and the expression of Bcl-2/Bax, survivin and NF-κB (Wei et al., 2012).

Radio-sensitizer

The combined treatment of radiation with OA significantly decreased the clonogenic growth of tumor cells and enhanced the numbers of intracellular MN compared to irradiation alone. Furthermore, it was found that the synthesis of cellular GSH was inhibited concomitantly with the down-regulation of γ-GCS activity. Therefore, the utilization of OA as a radio-sensitizing agent for irradiation-inducing cell death offers a potential therapeutic approach to treat cancer (Wang et al., 2013).

Prostate Cancer, Lung Cancer, Gastric Cancer, Breast Cancer

Twelve derivatives of oleanolic acid (OA) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC50=0.39 µM) and compound 28 displayed the best activity against A549 cell line (IC50=0.22 µM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines (Hao et al., 2013).

Hepatocellular Carcinoma

OA induced G2/M cell-cycle arrest through p21-mediated down-regulation of cyclin B1/cdc2. Cyclooxygenase-2 (COX-2) and p53 were involved in OA-exerted effect, and extracellular signal-regulated kinase-p53 signaling played a central role in OA-activated cascades responsible for apoptosis and cell-cycle arrest. OA demonstrated significant anti-tumor activities in hepatocellular carcinoma (HCC) in vivo and in vitro models. These data provide new insights into the mechanisms underlying the anti-tumor effect of OA (Wang et al., 2013).

References

Hao J, Liu J, Wen X, Sun H. (2013). Synthesis and cytotoxicity evaluation of oleanolic acid derivatives. Bioorg Med Chem Lett, 23(7):2074-7. doi: 10.1016/j.bmcl.2013.01.129.


StrŸh CM, JŠger S, Kersten A, et al. (2013). Triterpenoids amplify anti-tumoral effects of mistletoe extracts on murine B16.f10 melanoma in vivo. PLoS One, 8(4):e62168. doi: 10.1371/journal.pone.0062168.


Wang J, Yu M, Xiao L, et al. (2013). Radio-sensitizing effect of oleanolic acid on tumor cells through the inhibition of GSH synthesis in vitro. Oncol Rep, 30(2):917-24. doi: 10.3892/or.2013.2510.


Wang X, Bai H, Zhang X, et al. (2013). Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell-cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis, 34(6):1323-30. doi: 10.1093/carcin/bgt058.


Wei JT, Liu M, Liuz, et al. (2012). Oleanolic acid arrests cell-cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. Journal of Applied Toxicology, 33(8):756–765. doi: 10.1002/jat.2725


Wei J, Liu H, Liu M, et al. (2012). Oleanolic acid potentiates the anti-tumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol Rep, 28(4):1339-45. doi: 10.3892/or.2012.1921.

anti-tumor, anti-tumor activity, apoptosis, Chapter 7 Isolates and Cancer Research, cytotoxic, Melanoma, PC3, PC3 and DU145, Prostate cancer, Prostate cancer cell lines, Radio-sensitizer, radio-sensitizing, U251

Oleandrin

Cancer: Prostate, glioma, melanoma

Action: Radio-sensitizer

Anvirzel is an extract of Nerium oleander (L.) currently undergoing, as Anvirzelª Phase I clinical evaluation as a potential treatment for cancer. Two of the active components of Anvirzel are the cardiac glycosides, oleandrin and oleandrigenin.

Prostate Cancer

In continuing research on the anti-tumor activity of this novel plant extract, the relative abilities of oleandrin and oleandrigenin to inhibit FGF-2 export from two human prostate cancer cell lines, DU145 and PC3, were examined. An ELISA assay was utilized to determine the FGF-2 concentration in the cell culture medium before and after exposure to cardiac glycosides or the parent extract material Anvirzel.

Studies also were conducted with Anvirzel (a hot water extract of Nerium oleander, known as Anvirzelª) and ouabain (found in the ripe seeds of African plants Strophanthus gratus). Oleandrin (0.1 ng/mL) produced a 45.7% inhibition of FGF-2 release from PC3 cells and a 49.9% inhibition from DU145 cells. Non-cytotoxic concentrations (100 ng/mL) of Anvirzel produced a 51.9% and 30.8% inhibition of FGF-2 release, respectively, in the two cell lines. These results demonstrate that Anvirzel, like oleandrin, inhibited FGF-2 export in vitro from PC3 and DU145 prostate cancer cells in a concentration- and time-dependent fashion and may, therefore, contribute to the anti-tumor activity of this novel treatment for cancer (Smith et al., 2001).

Radio-sensitizers; Prostate Cancer

In the present study Nasu et al. (2002) explored the relative radio-sensitization potential of oleandrin, a cardiac glycoside contained within the plant extract known as Anvirzelª. The data show that oleandrin produces an enhancement of sensitivity of PC-3 human prostate cells to radiation; at a cell survival of 0.1, the enhancement factor was 1.32. The magnitude of radio-sensitization depended on duration of exposure of cells to drug prior to radiation treatment.

While a radio-sensitizing effect of oleandrin was evident with only 1 hour of cell exposure to drug, the effect greatly increased with 24 hours of oleandrin pre-treatment.

Activation was greatest when cells were exposed simultaneously to oleandrin and radiation. Inhibition of caspase-3 activation with Z-DEVD-FMK abrogated the oleandrin-induced enhancement of radiation response suggesting that both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 cell line.

Glioma, Melanoma

Twelve human tumor cell lines were chosen to examine determinants of human tumor cell sensitivity to cardiac glycosides. In vitro cell culture models of human glioma HF U251 and U251 cells as well as human parental and modified melanoma BRO cells were also included in these studies. Cardiac glycosides such as oleandrin, ouabain and bufalin increased expression of Na+, K+ -ATPase alpha 1 and therefore total Na+, K+ -ATPase activity, which is associated with increased cellular levels of glutathione. Additionally, an increased colony-forming ability was noted in cells with high levels of Na+, K+ -ATPase alpha 1 expression, suggesting that Na+, K+ -ATPase alpha 1 isoform may be actively involved in tumor growth and cell survival (Lin, Ho, & Newman, 2010)

References

Lin Y, Ho DH, Newman RA. (2010). Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+ -ATPase subunitst. J Exp Ther Oncol, 8(4):271-86.


Nasu S, Milas L, Kawabe S, Raju U, Newman R. (2002). Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. Cancer Letters, 185(2):145–151. doi:10.1016/S0304-3835(02)00263-X


Smith JA, Madden T, Vijjeswarapu M, Newman RA. (2001). Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by anvirzel and its cardiac glycoside component, oleandrin. Biochemical Pharmacology, 62(4):469-472. doi:10.1016/S0006-2952(01)00690-6.

Anti-angiogenic, anti-tumor, anti-tumor activity, apoptosis, BAX, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, Cytostatic, ER, G0/G1, G1, growth-inhibitory, Melanoma, Osteosarcoma, p21, p38, PARP, Sarcoma

Nelumbo Extract (NLE):Neferine

Cancer: Liver, osteosarcoma, breast, melanoma

Action: Anti-angiogenic, cytostatic

Neferine is a major bis-benzylisoquinoline alkaloid derived from the green seed embryos of the Indian lotus (Nelumbo nucifera (Gaertn.)).

Identification of natural products that have anti-tumor activity is invaluable to the chemo-prevention and therapy of cancer. The embryos of lotus (Nelumbo nucifera) seeds are consumed in beverage in some parts of the world for their presumed health-benefiting effects. Neferine is a major alkaloid component in lotus embryos.

Hepatitis

Experimental results suggest that neferine exhibited cytotoxicity against HCC Hep3B cells, but not against HCC Sk-Hep1 and THLE-3, a normal human liver cell line. Results demonstrated neferine induced ER stress and apoptosis, acting through multiple signaling cascades by the activation of Bim, Bid, Bax, Bak, Puma, caspases-3, -6, -7, -8 and PARP, and the protein expression levels of Bip, calnexin, PDI, calpain-2 and caspase-12 were also upregulated dramatically by neferine treatment.

These observations reveal that the therapeutic potential of neferine in treating HCC Hep3B cells, containing copies of hepatitis B virus (HBV) genomes (Yoon et al., 2013).

Osteosarcoma

It was found that neferine possessed a potent growth-inhibitory effect on human osteosarcoma cells, but not on non-neoplastic human osteoblast cells. The inhibitory effect of neferine on human osteosarcoma cells was largely attributed to cell-cycle arrest at G1. The up-regulation of p21 by neferine was due to an increase in the half-life of p21 protein. Zhang et al. (2012) showed that neferine treatment led to an increased phosphorylation of p21 at Ser130 that was dependent on p38. Their results for the first time showed a direct anti-tumor effect of neferine, suggesting that consumption of neferine may have cancer-preventive and cancer-therapeutic benefit.

Breast Cancer

Qualitative analysis showed that NLE contained several compounds, including polyphenols. The polyphenols identified in NLE consisted primarily of gallic acid, rutin, and quercetin. Cell cycle analysis revealed that breast cancer MCF-7 cells treated with NLE were arrested at the G0/G1 phase. In an in vivo analysis, treatment with NLE (0.5 and 1%) effectively reduced tumor volume and tumor weight in mice inoculated with MCF-7 cells compared to the control samples.

These results confirmed that cell-cycle arrest was sufficient to elicit tumor regression following NLE treatment (Yang et al., 2011).

Melanoma

Methanolic extracts from the flower buds and leaves of sacred lotus (Nelumbo nucifera) were found to show inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells. 3-30 µM nuciferine and N-methylasimilobine inhibited the expression of tyrosinase mRNA, 3-30 µM N-methylasimilobine inhibited the expression of TRP-1 mRNA, and 10-30 µM nuciferine inhibited the expression of TRP-2 mRNA (Nakamura et al., 2013).

References

Nakamura S, Nakashima S, Tanabe G, et al. (2013). Alkaloid constituents from flower buds and leaves of sacred lotus (Nelumbo nucifera, Nymphaeaceae) with melanogenesis inhibitory activity in B16 melanoma cells. Bioorg Med Chem, 21(3):779-87. doi: 10.1016/j.bmc.2012.11.038.


Yang MY, Chang YC, Chan KC et al. (2011). Flavonoid-enriched extracts from Nelumbo nucifera leaves inhibits proliferation of breast cancer in vitro and in vivo. European Journal of Integrative Medicine, 3(3):153-163. doi:10.1016/j.eujim.2011.08.008


Yoon JS, Kim HM, Yadunandam AK, et al. (2013). Neferine isolated from Nelumbo nucifera enhances anti-cancer activities in Hep3B cells: Molecular mechanisms of cell-cycle arrest, ER stress induced apoptosis and anti-angiogenic response. Phytomedicine, 20(11):1013–1022. doi:10.1016/j.phymed.2013.03.024.


Zhang XY, Liu ZJ, Xu B, et al. (2012). Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization. European Journal of Pharmacology, 677(1–3):47–54.

AhR, Akt, angiogenesis, Anti-cancer, anti-proliferative, anti-proliferative effect, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BCR, Breast cancer, CDK, CDK2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, CYP1A1, CYP1B1, FAK, G1, G2/M, Head and neck cancer, inflammation, inhibits angiogenesis, Isatis (L.) genus, Lung cancer, MCF-7, metastasis, Prostate cancer, RS4;11 and MV4;1, STAT3

Indirubin

Cancer:
Chronic myelogenous leukemia, lung, breast, head and neck, prostate, acute myeloid leukemia, prostate

Action: Aryl hydrocarbon Receptor (AhR) regulator, inhibits angiogenesis

Indirubin is the active component of many plants from the Isatis (L.) genus, including Isatis tinctoria (L.).

Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Indirubin and its analogues are potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell-cycle. These results have implications for therapeutic optimization of indigoids (Hoessel et al., 1999).

Formula; Huang Lian (Rhizoma Coptidis Recens), Huang Qin (Radix Scutellariae Baicalensis), Huang Bai (Cortex Phellodendri), Zhi Zi (Fructus Gardeniae Jasminoidis), Dang Gui (Radix Angelicae Sinensis), Lu Hui (Herba Aloes), Long Dan Cao (Radix Gentianae Longdancao), Da Huang (Radix et Rhizoma Rhei), Mu Xiang (Radix Aucklandiae Lappae), Qing Dai (Indigo Pulverata Levis), She Xiang (Secretio Moschus)

Leukemia

Indirubin, a 3, 2' bisindole isomer of indigo was originally identified as the active principle of a traditional Chinese preparation and has been proven to exhibit anti-leukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anti-cancer compounds accessible with strongly improved CDK inhibitory potential and with broad-spectrum anti-tumor activity.

This novel family of compounds holds strong promise for clinical anti-cancer activity and might be useful also in several important non-cancer indications, including Alzheimer's disease or diabetes (Eisenbrand et al., 2004).

Aryl Hydrocarbon Receptor (AhR) Regulator; Breast Cancer

The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), regulates expression of several phase I and phase II enzymes and is also involved in the regulation of cell proliferation. One putative endogenous ligand is indirubin, which was recently identified in human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of cytochromes P450 (CYP) 1A1 and 1B1. With 4 hours exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but the effects of indirubin, unlike those of TCDD, were transitory. Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6–9 hours post-exposure and had disappeared by 24 hours, whereas TCDD-induced activities remained elevated for at least 72 hours.

Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling by indirubin is likely to be transient and tightly controlled by the ability of indirubin to induce CYP1A1 and CYP1B1, and hence its own metabolism (Spink et al., 2003).

Chronic Myelogenous Leukemia (CML)

Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). In a study investigating its mechanism of action, indirubin derivatives (IRDs) were found to potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells.

Compound E804, which is the most potent in this series of IRDs, blocked Stat5 signaling in human K562 CML cells, imatinib-resistant human KCL-22 CML cells expressing the T315I mutant Bcr-Abl (KCL-22M), and CD34-positive primary CML cells from patients.

In sum, these findings identify IRDs as potent inhibitors of the SFK/Stat5 signaling pathway downstream of Bcr-Abl, leading to apoptosis of K562, KCL-22M and primary CML cells. IRDs represent a promising structural class for development of new therapeutics for wild type or T315I mutant Bcr-Abl-positive CML patients (Nam et al., 2012).

Lung Cancer

A novel indirubin derivative, 5'-nitro-indirubinoxime (5'-NIO), exhibits a strong anti-cancer activity against human cancer cells. Here, the 5'-NIO-mediated G1 cell-cycle arrest in lung cancer cells was associated with a decrease in protein levels of polo-like kinase 1 (Plk1) and peptidyl-prolyl cis/trans isomerase Pin1. These findings suggest that 5'-NIO have potential anti-cancer efficacy through the inhibition of Plk1 or/and Pin1 expression (Yoon et al., 2012).

The control lung tissue showed a normal architecture with clear alveolar spaces. Interestingly, the indirubin-3-monoxime treated groups showed reduced adenocarcinoma with appearance of alveolar spaces. Transmission Electron Microscopic (TEM) studies of lung sections of [B(α)P]-induced lung cancer mice showed the presence of phaemorphic cells with dense granules and increased mitochondria.

The lung sections of mice treated with indirubin-3-monoxime showed the presence of shrunken, fragmented, and condensed nuclei implying apoptosis. The effects were dose-dependent and prominent in 10 mg/kg/5 d/week groups, suggesting the therapeutic role of indirubin analogue against this deadly human malignancy. These results indicate that indirubin-3-monoxime brings anti-tumor effect against [B(α)P]-induced lung cancer by its apoptotic action in A/J mice (Ravichandran et al., 2010).

Head and Neck Cancer

The effects of 5'-nitro-indirubinoxime (5'-NIO), an indirubin derivative, on metastasis of head and neck cancer cells were investigated and the underlying molecular mechanisms involved in this process explored.

After treatment of head and neck cancer cells with 5'-NIO, cell metastatic behaviors such as colony formation, invasion, and migration were inhibited in a concentration-dependent manner. 5'-NIO inhibited the beta1 Integrin/FAK/Akt pathway which can then facilitate invasion and/or migration of cancer cells through the extracellular matrix (ECM). Moreover, treatment of head and neck cancer cell with Integrin β1 siRNA or FAK inhibitor effectively inhibited the invasion and migration, suggesting their regulatory role in invasiveness and migration of head and neck cancer cells. It was concluded that 5'-NIO inhibits the metastatic ability of head and neck cancer cells by blocking the Integrin β1/FAK/Akt pathway (Kim et al., 2011).

Prostate Cancer; Inhibits Angiogenesis

Indirubin, the active component of a traditional Chinese herbal medicine, Banlangen, has been shown to exhibit anti-tumor and anti-inflammation effects; however, its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is unknown.

To address this shortfall in the existing research, it was identified that indirubin inhibited prostate tumor growth through inhibiting tumor angiogenesis. It was found that indirubin inhibited angiogenesis in vivo. The inhibition activity of indirubin in endothelial cell migration, tube formation and cell survival in vitro has also been shown. Furthermore, indirubin suppressed vascular endothelial growth factor receptor 2-mediated Janus kinase (JAK)/STAT3 signaling pathway. This study provided the first evidence for anti-tumor angiogenesis activity of indirubin and the related molecular mechanism.

These investigations suggest that indirubin is a potential drug candidate for angiogenesis-related diseases (Zhang et al., 2011).

Acute Myeloid Leukemia

Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4;11 and MV4;11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5'-substituted indirubin derivatives, 5-fluoro analog, 13 exhibited potent inhibitory activity at FLT3 (IC(50)=15 nM) with more than 100-fold selectivity versus 6 other kinases and potent anti-proliferative effect for MV4;11 cells (IC(50)=72 nM) with 30-fold selectivity versus RS4;11 cells.

Cell cycle analysis indicated that compound 13 induced cell-cycle arrest at G(0)/G(1) phase in MV4;11 cells (Choi et al., 2010).

References

Choi SJ, Moon MJ, Lee SD, et al. (2010). Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells. Bioorg Med Chem Lett, 20(6):2033-7.


Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S. (2004). Molecular mechanisms of indirubin and its derivatives: novel anti-cancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol, 130(11):627-35


Hoessel R, Leclerc S, Endicott JA, et al. (1999). Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol, 1(1):60-7.


Kim SA, Kwon SM, Kim JA, et al. (2011). 5'-Nitro-indirubinoxime, an indirubin derivative, suppresses metastatic ability of human head and neck cancer cells through the inhibition of Integrin β 1/FAK/Akt signaling. Cancer Lett, 306(2):197-204.


Nam S, Scuto A, Yang F, et al. (2012). Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol Oncol, 6(3):276-83.


Ravichandran K, Pal A, Ravichandran R. (2010). Effect of indirubin-3-monoxime against lung cancer as evaluated by histological and transmission electron microscopic studies. Microsc Res Tech, 73(11):1053-8.


Spink BC, Hussain MM, Katz BH, Eisele L, Spink DC. (2003). Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin. Biochem Pharmacol, 66(12):2313-21.


Yoon HE, Kim SA, Choi HS, et al. (2012). Inhibition of Plk1 and Pin1 by 5'-nitro-indirubinoxime suppresses human lung cancer cells. Cancer Lett, 316(1):97-104.


Zhang X, Song Y, Wu Y, et al. (2011). Indirubin inhibits tumor growth by anti-tumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int J Cancer, 129(10):2502-11. doi: 10.1002/ijc.25909.

angiogenesis, Anti-cancer, Anti-cancer effect, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, BCR, Breast cancer, CAM, CDC2, CDC25C, CDK4, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Endometrial cancer, ER, ER modulator, ERK, G2/M, Hec1A, KIP1, MCF-7, MCF7, MDA-MB-453, p16, p27, PC3, Pro-apoptotic, Radio-sensitizer, several species of the genus Epimedium

Icaritin

Cancer:
Endometrial., chronic myeloid leukemia, prostate, breast

Action: Radio-sensitizer, cell-cycle arrest, ER modulator

Icaritin is a compound in several species of the genus Epimedium (L.).

Cell-cycle Arrest

Icariin and icaritin with prenyl group have been demonstrated to have selective estrogen receptor modulating activities. Icaritin-induced growth inhibition was associated with G(1) arrest (P<0.05), and G(2)-M arrest depending upon doses. Consistent with G(1) arrest, icaritin increased protein expressions of pRb, p27(Kip1) and p16(Ink4a), while showing decrease in phosphorylated pRb, Cyclin D1 and CDK4.

Comparatively, icariin has much lower effects on PC-3 cells and showed only weak G(1) arrest, suggesting a possible structure-activity relationship. These findings suggested a novel anti-cancer efficacy of icaritin mediated selectively via induction of cell-cycle arrest but not associated with estrogen receptors in PC-3 cells (Huang et al., 2007).

Estrogen Receptor (ER) Modulator; Endometrial Cancer

Icaritin has selective estrogen receptor (ER) modulating activities, and posseses anti-tumor activity. The effect of icaritin on cell growth of human endometrial cancer Hec1A cells was investigated and it was found that icaritin potently inhibited proliferation of Hec1A cells. Icaritin also induced cell apoptosis accompanied by activation of caspases. Icaritin treatment also induced expression of pro-apoptotic protein Bax with a concomitant decrease of Bcl-2 expression.

These results demonstrate that icaritin induced sustained ERK 1/2 activation and inhibited growth of endometrial cancer Hec1A cells, and provided a rationale for preclinical and clinical evaluation of icaritin for endometrial cancer therapy (Tong et al., 2011).

Breast cancer

In research carried out to probe breast cancer cell growth mechanisms, icaritin has been found to strongly inhibit the growth of breast cancer MDA-MB-453 and MCF7 cells. At concentrations of 2–3 µM, icaritin induced cell-cycle arrest at the G2/M phase accompanied by a down-regulation of the expression levels of the G2/M regulatory proteins such as cyclinB, cdc2 and cdc25C.

Icaritin at concentrations of 4–5 µM, however, induced apoptotic cell death. In addition, icaritin also induced a sustained phosphorylation of extracellular signal-regulated kinase (ERK) in these breast cancer cells.

Icaritin more potently inhibited growth of the breast cancer stem/progenitor cells compared to anti-estrogen tamoxifen. These results indicate that icaritin is a potent growth inhibitor for breast cancer cells and provides a rationale for preclinical and clinical evaluations of icaritin for breast cancer therapy (Guo et al., 2011).

Radio-sensitizer

The combination of Icaritin at 3 µM or 6 µM with 6 or 8 Gy of ionizing radiation (IR) in the clonogenic assay yielded an ER (enhancement ratio) of 1.18 or 1.28, CI (combination index) of 0.38 or 0.19 and DRI (dose reducing index) of 2.51 or 5.07, respectively. These findings strongly suggest that Icaritin exerted a synergistic killing effect with radiation on the tumor cells. It suppressed angiogenesis in chick embryo chorioallantoic membrane (CAM) assay. These results, taken together, indicate Icaritin is a new radio-sensitizer and can enhance anti-cancer effect of IR or other therapies (Hong et al., 2013).

Chronic Myeloid Leukemia (CML)

The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML. Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis, and promoted the erythroid differentiation of K562 cells in a time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis (Zhu et al., 2011).

References

Guo YM, Zhang XT, Meng J, Wang ZY. (2011). An anti-cancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase (ERK) pathway and inhibits growth of breast cancer cells. European Journal of Pharmacology, 658(2–3):114–122. doi:10.1016/j.ejphar.2011.02.005.


Hong J, Zhang Z, Lv W, et al. (2013). Icaritin Synergistically Enhances the Radiosensitivity of 4T1 Breast Cancer Cells. PLoS One, 8(8):e71347. doi: 10.1371/journal.pone.0071347.


Huang X, Zhu D, Lou Y. (2007). A novel anti-cancer agent, icaritin, induced cell growth inhibition, G1 arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells. Eur J Pharmacol, 564(1-3):26-36.


Tong JS, Zhang QH, Huang X, et al. (2011). Icaritin Causes Sustained ERK1/2 Activation and Induces Apoptosis in Human Endometrial Cancer Cells. PLoS ONE, 6(3): e16781. doi:10.1371/journal.pone.0016781.


Zhu JF, Li ZJ, Zhang GS, et al. (2011). Icaritin shows potent anti-leukemia activity on chronic myeloid leukemia in vitro and in vivo by regulating MAPK/ERK/JNK and JAK2/STAT3 /AKT signalings. PLoS One, 6(8):e23720. doi: 10.1371/journal.pone.0023720.