Category Archives: cytotoxic

Cervical cancer, Chapter 7 Isolates and Cancer Research, cytotoxic, PR

Corydalis cava

Cancer: Cervical

Action: none noted

Cervical Cancer

Nucleolytic proteins were isolated from the tubers of C. cava by separation on a heparin column and tested for DNase activity. Protein fractions showing nucleolytic activity were tested for cytotoxic activity in human cervical carcinoma HeLa cells. The studied protein fractions showed an inhibiting effect on mitochondrial activity of HeLa cells, depending on the administered dose of proteins. The most pronounced effect was obtained with the highest concentration of the protein (167 ng/ml) – 43.45 ± 3% mitochondrial activity of HeLa cells were inhibited. The cytotoxic effect of studied proteins toward HeLa cell line cells was evident and dependent on increasing dose of the protein. This represents the first investigation of the effect of purified PR proteins from tuber extracts of a pharmacologically active plant (C. cava) on HeLa cell lines (Nawro et al., 2010).

References

Nawrot R, Wolun-Cholewa M, Bialas W, et al. (2010). Cytotoxic activity of proteins isolated from extracts of Corydalis cava tubers in human cervical carcinoma HeLa cells. BMC Complementary and Alternative Medicine, 10:78. doi:10.1186/1472-6882-10-78.

Anti-cancer, anti-inflammatory, anti-tumor, Apoptotic, BAX, Bcl-2, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, Chemotherapy, Crataegus pinnatifida, cytotoxic, Glioblastoma, HeLa, HER2, HER2-positive, IL-10, Immunosuppressive activity, K562, Lagerstroemia speciosa, metastasis, Osteosarcoma, PKC, S, Sarcoma, STAT3

Corosolic acid

Cancer:
Myeloid leukemia, cervical., glioblastoma, gastric, sarcoma

Action: Immunosuppressive activity

Corosolic Acid is isolated from Lagerstroemia speciosa [(L.) Pers.] and Crataegus pinnatifida var. psilosa (C. K. Schneider).

Sarcoma; Immunosuppressive Activity

The results from an in vivo study showed that Corosolic acid (CA) administration did not suppress the tumor proliferation index, but significantly impaired subcutaneous tumor development and lung metastasis.

CA administration inhibited signal transducer and activator of transcription-3 (Stat3) activation and increased in the number of infiltrating lymphocytes in tumor tissues. Ex vivo analysis demonstrated that a significant immunosuppressive effect of MDSC in tumor-bearing mice was abrogated and the mRNA expressions of cyclooxygenase-2 and CCL2 in MDSC were significantly decreased by CA administration.

Furthermore, CA enhanced the anti-tumor effects of adriamycin and cisplatin in vitro. Since Stat3 is associated with tumor progression not only in osteosarcoma, but also in other malignant tumors, these findings indicate that CA might be widely useful in anti-cancer therapy by targeting the immunosuppressive activity of MDSC and through its synergistic effects with anti-cancer agents (Horlad et al., 2013).

Cervical Cancer

Xu et al. (2009) investigated the response of human cervix adenocarcinoma HeLa cells to Corosolic acid (CRA) treatment. These results showed that CRA significantly inhibited cell viability in both a dose- and a time-dependent manner. CRA treatment induced S cell-cycle arrest and caused apoptotic death in HeLa cells. It was found that CRA increased in Bax/Bcl-2 ratios by up-regulating Bax expression, disrupted mitochondrial membrane potential and triggered the release of cytochrome c from mitochondria into the cytoplasm.

These results, taken together, indicate CRA could have strong potentials for clinical application in treating human cervix adenocarcinoma and improving cancer chemotherapy.

Glioblastoma

Tumor-associated macrophages (TAMs) of M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with glioblastoma.

The natural compounds possessing inhibitory effects on M2 polarisation in human monocyte-derived macrophages were investigated. Among 130 purified natural compounds examined, corosolic acid significantly inhibited the expression of CD163, one of the phenotype markers of M2 macrophages, as well as suppressed the secretion of IL-10, one of the anti-inflammatory cytokines preferentially produced by M2 macrophages, thus suggesting that corosolic acid suppresses M2 polarisation of macrophages.

Furthermore, corosolic acid inhibited the proliferation of glioblastoma cells, U373 and T98G, and the activation of Signal transducer and activator of transcription-3 (STAT3) and Nuclear Factor-kappa B (NF-κB), in both human macrophages and glioblastoma cells. These results indicate that corosolic acid suppresses the M2 polarisation of macrophages and tumor cell proliferation by inhibiting both STAT3 and NF-κB activation. Therefore, corosolic acid may be a new tool for tumor prevention and therapy (Fujiwara et al., 2010).

Gastric Cancer

Corosolic acid (CRA) suppresses HER2 expression, which in turn promotes cell-cycle arrest and apoptotic cell death of gastric cancer cells, providing a rationale for future clinical trials of CRA in the treatment of HER2-positive gastric cancers. CRA combined with adriamycin and 5-fluorouracil enhanced this growth inhibition, but not with docetaxel and paclitaxel (Lee et al., 2010).

Leukemia

Corosolic acid displayed about the same potent cytotoxic activity as ursolic acid against several human cancer cell lines. In addition, the compound displayed antagonistic activity against the phorbol ester-induced morphological modification of K-562 leukemic cells, indicating the suppression of protein kinase C (PKC) activity by the cytotoxic compound (Ahn et al., 1998).

References

Ahn KS, Hahm MS, Park EJ, Lee HK, Kim IH. (1998). Corosolic acid isolated from the fruit of Crataegus pinnatifida var. psilosa is a protein kinase C inhibitor as well as a cytotoxic agent. Planta Med, 64(5):468-70.


Fujiwara Y, Komohara Y, Ikeda T, Takeya M. (2010). Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B in tumor cells and tumor-associated macrophages. Cancer Science. doi: 10.1111/j.1349-7006.2010.01772.x


Horlad H, Fujiwara Y, Takemura K, et al. (2013). Corosolic acid impairs tumor development and lung metastasis by inhibiting the immunosuppressive activity of myeloid-derived suppressor cells. Molecular Nutrition & Food Research, 57(6):1046-1054. doi: 10.1002/mnfr.201200610


Lee MS, Cha EY, Thuong PT, et al. (2010). Down-regulation of human epidermal growth factor receptor 2/neu oncogene by corosolic acid induces cell-cycle arrest and apoptosis in NCI-N87 human gastric cancer cells. Biol Pharm Bull, 33(6):931-7.


Xu YF, Ge RL, Du J, et al. (2009). Corosolic acid induces apoptosis through mitochondrial pathway and caspases activation in human cervix adenocarcinoma HeLa cells. Cancer Letters, 284(2):229-237. doi:10.1016/j.canlet.2009.04.028.

Akt, anti-inflammatory, anti-tumor, anti-tumor activity, apoptosis, Caesalpinia coriaria, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, cytotoxic, ERK, G2/M, Hep3B, hepato-protective, Ovarian cancer, Ovarian cancer cell lines, Phyllanthus niruri, Punica granatum, Radio-protective, SKOv3ip,Hey and HO-8910PM

Corilagin

Cancer: Ovarian, hepatocellular carcinoma

Action: Radio-protective

Corilagin is isolated from Phyllanthus niruri (L.), Punica granatum (Linnaeus), Caesalpinia coriaria [(Jacq.) Willd.], Alchornea glandulosa (Poepp. & Endl.).

Ovarian Cancer

Phyllanthus niruri L. is a well-known hepato-protective and anti-viral medicinal herb. Recently, Jia et al. (2013) identified Corilagin as a major active component with anti-tumor activity in this herbal medicine. Corilagin is a member of the tannin family that has been discovered in many medicinal plants and has been used as an anti-inflammatory agent.

The ovarian cancer cell lines SKOv3ip, Hey and HO-8910PM were treated with Corilagin. Corilagin inhibited the growth of the ovarian cancer cell lines SKOv3ip and Hey, with IC50 values of less than 30 muM, while displaying low toxicity against normal ovarian surface epithelium cells, with IC50 values of approximately 160 muM. Corilagin induced cell-cycle arrest at the G2/M stage and enhanced apoptosis in ovarian cancer cells.

In contrast, a reduction of TGF-beta secretion was not observed in cancer cells treated with the cytotoxic drug Paclitaxel, suggesting that Corilagin specifically targets TGF-beta secretion. Corilagin blocked the activation of both the canonical Smad and non-canonical ERK/AKT pathways.

Corilagin extracted from Phyllanthus niruri L. acts as a natural., effective therapeutic agent against the growth of ovarian cancer cells via targeted action against the TGF-beta/AKT/ERK/Smad signaling pathways (Jia et al., 2013).

Hepatocellular Carcinoma

Corilagin is considerably effective to retard the in vivo growth of xenografted Hep3B hepatocellular carcinoma. A significant inhibition of tumor growth was observed when treated mice are compared with control groups. Furthermore, analysis of enzymes markers of liver function, including alanine aminotransferase and asparate aminotransferase, suggested that current therapeutic dosage of corilagin did not exert adverse effect on liver (Hau et al., 2010).

Radio-protective

Corilagin, a member of the tannin family, inhibits NF-kappaB pathway activation. In the present study, Dong et al. (2010) examined the inhibitory effects of corilagin on radiation-induced microglia activation. Their data suggest that corilagin inhibits radiation-induced microglia activation via suppression of the NF-kappaB pathway and the compound is a potential treatment for radiation-induced brain injury (RIBI) (Dong et al., 2010).

References

Dong XR, Luo M, Fan L, et al. (2010). Corilagin inhibits the double strand break-triggered NF-kappaB pathway in irradiated microglial cells. Int J Mol Med, 25(4):531-6.


Hau DK, Zhu GY, Leung AK, et al. (2010) In vivo anti-tumor activity of corilagin on Hep3B hepatocellular carcinoma. Phytomedicine, 18(1):11-5. doi: 10.1016/j.phymed.2010.09.001.


Jia LQ, Jin HY, Zhou JY, et al. (2013). A potential anti-tumor herbal medicine, Corilagin, inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways. BMC Complementary and Alternative Medicine, 13:33. doi:10.1186/1472-6882-13-33

4T1, angiogenesis, Anti-angiogenic, Anti-cancer, anti-carcinogenic, anti-oxidative, apoptosis, bFGF, Breast cancer, CAM, Chapter 7 Isolates and Cancer Research, Curcuma zedoaria, cytotoxic, metastasis, PC3, Prostate cancer, ROS

Campesterol

Cancer: Breast, prostate

Action: Anti-angiogenic, anti-oxidative

Anti-angiogenic

Campesterol, a plant sterol in nature, is known to have cholesterol-lowering and anti-carcinogenic effects. Since angiogenesis is essential for cancer, it was surmised that an anti-angiogenic effect may be involved in the anti-cancer action of this compound. This study investigated the effect of campesterol on basic fibroblast growth factor (bFGF)-induced angiogenesis in vitro in human umbilical vein endothelial cells (HUVECs) and an in vivo chorioallantoic membrane (CAM) model.

Campesterol, isolated from an ethylacetate fraction of Chrysanthemum coronarium (L.), showed a weak cytotoxicity in non-proliferating HUVECs. Within the non-cytotoxic concentration range, campesterol significantly inhibited the bFGF-induced proliferation and tube formation of HUVECs in a concentration-dependent manner, without affecting the motility of HUVECs. Furthermore, campesterol effectively disrupted the bFGF-induced neovascularization in chick chorioallantoic membranes (CAM) in vivo.

Taken together, these results support a potential anti-angiogenic action of campesterol via an inhibition of endothelial cell proliferation and capillary differentiation (Choi et al., 2007).

Metastatic Breast Cancer

Porphyra dentata, an edible red macroalgae, is used as a folk medicine in Asia. The in vitro and in vivo protective effects of a sterol fraction from P. dentata against breast cancer, linked to tumor-induced myeloid derived-suppressor cells (MDSCs), was investigated.

A sterol fraction containing cholesterol, β-sitosterol, and campesterol was prepared by solvent fractionation of methanol extract of P. dentata   in silica gel column chromatography. This sterol fraction in vitro significantly inhibited cell growth and induced apoptosis in 4T1 metastatic breast cancer cells. Intraperitoneal injection of this sterol fraction at 10 and 25  mg/kg body weight into 4T1 cell-implanted tumor BALB/c mice significantly inhibited the growth of tumor nodules and increased the survival rate of mice.

Two likely mechanisms for this effect can be suggested. First, the sample might cause the apoptosis of 4T1 cells. The other possible mechanism is that the sample may down-regulate the suppressive activity of MDSCs by affecting their ROS accumulation and arginase activity. This inhibition would be consistent with the use of Porphyra dentata as a folk medicine to treat inflammatory disorders and also for breast cancer (Kazlowska, Lin, Chang & Tsai, 2013).

Prostate Cancer

In the in vitro studies, both beta-sitosterol and campesterol inhibited the growth of human prostate cancer (PC-3) cells by 70% and 14%, respectively, while cholesterol supplementation increased the growth by 18% when compared with controls. Phytosterols (PS) mixture inhibited the invasion of PC-3 cells into Matrigel-coated membranes by 78% while cholesterol increased it by 43% as compared with the cells in the control media. PS supplementation reduced the binding of PC-3 cells to laminin by 15-38% and fibronectin by 23% while cholesterol increased binding to type IV collagen by 36%. It was concluded that PS indirectly (in vivo as a dietary supplement) and directly (in tissue culture media) inhibited the growth and metastasis of PC-3 cells (Awad et al., 2001).

References

Awad AB, Fink CS, Williams H, Kim U. (2001). In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. Eur J Cancer Prev, 10(6):507-13.


Choi JM, Lee EO, Lee HJ, et al. (2007). Identification of campesterol from chrysanthemum coronarium l. and its anti-angiogenic activities. Phytotherapy Research, 21(10), 954-959.


Kazlowska K, Lin HTV, Chang SH, Tsai GJ. (2013). In vitro and in vivo anti-cancer effects of sterol fraction from red algae porphyra. Evidence-Based Complementary and Alternative Medicine, 2013(2013), 493869. http://dx.doi.org/10.1155/2013/493869.

A2058, Akt, anti-carcinogenic, anti-inflammatory, Anti-metastatic, anti-mitogenic, anti-oxidant, anti-proliferative, apoptosis, Apoptotic, Breast cancer, Breast cancer cell lines, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Cytostatic, cytotoxic, EMT, ER, FAK, honeybee hives, Immune, Immunomodulatory, inflammation, inhibits NF-κB, JNK, Lung cancer, MAPK, MCF-7/Adr, MCF-7/wt, Mcl-1, Melanoma, Oral cancer, p38, p65, PANC-1, Pancreatic cancer, Prostate cancer, ROS, S, SCC-9, TIMP-2, TNF, Twist

Caffeic acid phenethyl ester (CAPE)

Cancer:
Breast, prostate, leukemia, cervical., oral., melanoma

Action: EMT, anti-mitogenic, anti-carcinogenic, anti-inflammatory, immunomodulatory

Anti-mitogenic, Anti-carcinogenic, Anti-inflammatory, Immunomodulatory Properties

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties. A variety of in vitro pharmacology for CAPE has been reported. A study using CAPE showed a positive effect on reducing carcinogenic incidence. It is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties in vitro (Orban et al., 2000) Another study also showed that CAPE suppresses acute immune and inflammatory responses and holds promise for therapeutic uses to reduce inflammation (Huang et al., 1996).

Caffeic acid phenethyl ester (CAPE) specifically inhibits NF-κB at µM concentrations and shows ability to stop 5-lipoxygenase-catalyzed oxygenation of linoleic acid and arachidonic acid. Previous studies have demonstrated that CAPE exhibits anti-oxidant, anti-inflammatory, anti-proliferative, cytostatic, anti-viral., anti-bacterial., anti-fungal., and, most importantly, anti-neoplastic properties (Akyol et al., 2013).

Multiple Immunomodulatory and Anti-inflammatory Activities

The results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active.

Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and anti-inflammatory activities (Natarajan et al., 1996).

Breast Cancer

Aqueous extracts from Thymus serpyllum (ExTs), Thymus vulgaris (ExTv), Majorana hortensis (ExMh), and Mentha piperita (ExMp), and the phenolic compounds caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictiol-7-O-rutinoside (Er), and arbutin (Ab), were tested on two human breast cancer cell lines: Adriamycin-resistant MCF-7/Adr and wild-type MCF-7/wt.

ExMh showed the highest cytotoxicity, especially against MCF-7/Adr, whereas ExMp was the least toxic; particularly against MCF-7/wt cells. RA and LA exhibited the strongest cytotoxicity against both MCF-7 cell lines, over 2-fold greater than CA and Lgr, around 3-fold greater than Er, and around 4- to 7-fold in comparison with Lr and Ab. Except for Lr and Ab, all other phytochemicals were more toxic against MCF-7/wt, and all extracts exhibited higher toxicity against MCF-7/Adr. It might be concluded that the tested phenolics exhibited more beneficial properties when they were applied in the form of extracts comprising their mixtures (Berdowska et al., 2013).

Prostate Cancer

Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. CAPE-induced inhibition of AKT phosphorylation was more prominent (1.7-folds higher) in cells expressing ER-α such as PC-3 compared to LNCaP. In conclusion, CAPE enhances the anti-proliferative and cytotoxic effects of DOC and PTX in prostate cancer cells (Tolba et al., 2013).

EMT, Prostate Cancer

CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by down-regulation of vimentin and Twist 2 expression (Chen et al., 2013).

CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells (Lin et al., 2013). Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities (Liu et al., 2013).

Cervical Cancer

CAPE preferentially induced S- and G2 /M-phase cell-cycle arrests and initiated apoptosis in human cervical cancer lines. The effect was found to be associated with increased expression of E2F-1, as there is no CAPE-mediated induction of E2F-1 in the pre-cancerous cervical Z172 cells. CAPE also up-regulated the E2F-1 target genes cyclin A, cyclin E and apoptotic protease activating of factor 1 (Apaf-1) but down-regulated cyclin B and induced myeloid leukemia cell differentiation protein (Mcl-1) (Hsu et al., 2013).

Oral Cancer

CAPE attenuated SCC-9 oral cancer cells migration and invasion at noncytotoxic concentrations (0  µM to 40 µM). CAPE exerted its inhibitory effects on MMP-2 expression and activity by upregulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and potently decreased migration by reducing focal adhesion kinase (FAK) phosphorylation and the activation of its downstream signaling molecules p38/MAPK and JNK (Peng et al., 2012).

Melanoma

CAPE is suggested to suppress reactive-oxygen species (ROS)-induced DNA strand breakage in human melanoma A2058 cells when compared to other potential protective agents. CAPE can be applied not only as a chemo-preventive agent but also as an anti-metastatic therapeutic agent in lung cancer and because CAPE is a nuclear factor-κB (NF-κB) inhibitor and 5α reductase inhibitor, it has potential for the treatment of prostate cancer (Ozturk et al., 2012).

References

Akyol S, Ozturk G, Ginis Z, et al. (2013). In vivo and in vitro antõneoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives. Nutr Cancer, 65(4):515-26. doi: 10.1080/01635581.2013.776693.


Berdowska I, Ziel iński B, Fecka I, et al. (2013). Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. Food Chem, 15;141(2):1313-21. doi: 10.1016/j.foodchem.2013.03.090.


Chen MJ, Shih SC, Wang HY, et al. (2013). Caffeic Acid phenethyl ester inhibits epithelial-mesenchymal transition of human pancreatic cancer cells. Evid Based Complement Alternat Med, 2013:270906. doi: 10.1155/2013/270906.


Hsu TH, Chu CC, Hung MW, et al. (2013). Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells. FEBS J, 280(11):2581-93. doi: 10.1111/febs.12242.


Huang MT, Ma W, Yen P, et al. (1996). Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis, 17(4):761–5. doi:10.1093/carcin/17.4.761.


Lin HP, Lin CY, Liu CC, et al. (2013). Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int J Mol Sci, 14(3):5264-83. doi: 10.3390/ijms14035264.


Liu CC, Hsu JM, Kuo LK, et al. (2013). Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer. Med Hypotheses, 80(5):617-9. doi: 10.1016/j.mehy.2013.02.003.


Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB. (1996). Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA, 93(17):9090-5.


Orban Z, Mitsiades N, Burke TR, Tsokos M, Chrousos GP. (2000). Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation, 7(2): 99–105. doi:10.1159/000026427.


Ozturk G, Ginis Z, Akyol S, et al. (2012). The anti-cancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci, 16(15):2064-8.


Peng CY, Yang HW, Chu YH, et al. (2012). Caffeic Acid phenethyl ester inhibits oral cancer cell metastasis by regulating matrix metalloproteinase-2 and the mitogen-activated protein kinase pathway. Evid Based Complement Alternat Med, 2012:732578. doi: 10.1155/2012/732578.


Tolba MF, Esmat A, Al-Abd AM, et al. (2013). Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells. IUBMB Life, 65(8):716-29. doi: 10.1002/iub.1188.

Anti-cancer, anti-tumor, Breast cancer, Chapter 7 Isolates and Cancer Research, cytotoxic, ER, ER-negative, ER-positive, ROS

Bezielle

Cancer: Metastatic and ER-negative Breast

Action: Anti-cancer

Breast Cancer

Bezielle is an orally administered aqueous extract of Scutellaria barbata for treatment of advanced and metastatic breast cancer. Phase I trials showed promising tolerability and efficacy. In our study, we used a combined proteomic-metabolomic approach to investigate the molecular pathways affected by Bezielle in ER-positive BT474 and ER-negative SKBR3 cell lines. Bezielle's ability to induce oxidative stress was associated with the changes in expression of redox potential maintaining enzymes: glutathione- and thioredoxin-related proteins and peroxiredoxins. In regards to cell metabolism, decreased expression of α-enolase was associated with a reduction of de novo (13) C-lactate formation.

By inhibiting glucose metabolism, cells reacted by lowering the expression of glucose transporters and resulting in decreased intracellular glucose concentration. Decreased expression of fatty acid synthase and reduced concentration of phosphocholine indicated considerable changes in phospholipid metabolism. Ultimately, by inhibiting the major energy-producing pathways, Bezielle caused depletion of ATP and NAD(H). Both cell lines were responsive, thus suggesting that Bezielle has the potential to be effective against ER-negative breast cancers. In conclusion, Bezielle's cytotoxicity toward cancer cells is primarily based on inhibition of metabolic pathways that are preferentially activated in tumor cells thus explaining its specificity for cancer cells (Klawitter et al., 2011).

Anti-cancer

Chen et al. (2012) found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. They isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. The results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis.

Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells.

Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it (Chen et al., 2012).

References

Chen V, Staub RE, Baggett S, et al. (2012). Identification and analysis of the active phytochemicals from the anti-cancer botanical extract Bezielle. PLoS One, 7(1):e30107. doi: 10.1371/journal.pone.0030107.


Klawitter J, Klawitter J, Gurshtein J, et al. (2011). Bezielle (BZL101)-induced oxidative stress damage followed by redistribution of metabolic fluxes in breast cancer cells: a combined proteomic and metabolomic study. Int J Cancer. 129(12):2945-57. doi: 10.1002/ijc.25965.

A549 cells, angiogenesis, Anti-angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BAX, Bcl-2, Bcl-xL, c-Jun, CAM, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, cytotoxic, DUBs, G0/G1, G1, G1/S, Glioblastoma, growth-inhibitory, HT-29, IL-2, Immune, induces apoptosis, Ki-67, Leukemia, Lung cancer, MAPK, Mcl-1, Medulloblastoma, Melanoma, metastasis, Neuroblastoma, Nitric Oxide, Ovarian cancer, p21, p38, p53, Pancreatic cancer, Pro-apoptotic, Prostate cancer, radiotherapy, Rectal cancer, Rhabdomyosarcoma, ROS, Sarcoma, SK-N-AS, TNF, VEGF, VEGF

Betulin and Betulinic acid

Cancer:
Neuroblastoma, medulloblastoma, glioblastoma, colon, lung, oesophageal, leukemia, melanoma, pancreatic, prostate, breast, head & neck, myeloma, nasopharyngeal, cervical, ovarian, esophageal squamous carcinoma

Action: Anti-angiogenic effects, induces apoptosis, anti-oxidant, cytotoxic and immunomodifying activities

Betulin is a naturally occurring pentacyclic triterpene found in many plant species including, among others, in Betula platyphylla (white birch tree), Betula X caerulea [Blanch. (pro sp.)], Betula cordifolia (Regel), Betula papyrifera (Marsh.), Betula populifolia (Marsh.) and Dillenia indica L . It has anti-retroviral., anti-malarial., and anti-inflammatory properties, as well as a more recently discovered potential as an anti-cancer agent, by inhibition of topoisomerase (Chowdhury et al., 2002).

Betulin is found in the bark of several species of plants, principally the white birch (Betula pubescens ) (Tan et al., 2003) from which it gets its name, but also the ber tree (Ziziphus mauritiana ), selfheal (Prunella vulgaris ), the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas , a member of the persimmon family, Tetracera boiviniana , the jambul (Syzygium formosanum ) (Zuco et al., 2002), flowering quince (Chaenomeles sinensis ) (Gao et al., 2003), rosemary (Abe et al., 2002) and Pulsatilla chinensis (Ji et al., 2002).

Anti-cancer, Induces Apoptosis

The in vitro characterization of the anti-cancer activity of betulin in a range of human tumor cell lines (neuroblastoma, rhabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukaemia and multiple myeloma), and in primary tumor cultures isolated from patients (ovarian carcinoma, cervical carcinoma and glioblastoma multiforme) was carried out to probe its anti-cancer effect. The remarkable anti-proliferative effect of betulin in all tested tumor cell cultures was demonstrated. Furthermore, betulin altered tumor cell morphology, decreased their motility and induced apoptotic cell death. These findings demonstrate the anti-cancer potential of betulin and suggest that it may be applied as an adjunctive measure in cancer treatment (Rzeski, 2009).

Lung Cancer

Betulin has also shown anti-cancer activity on human lung cancer A549 cells by inducing apoptosis and changes in protein expression profiles. Differentially expressed proteins explained the cytotoxicity of betulin against human lung cancer A549 cells, and the proteomic approach was thus shown to be a potential tool for understanding the pharmacological activities of pharmacophores (Pyo, 2009).

Esophageal Squamous Carcinoma

The anti-tumor activity of betulin was investigated in EC109 cells. With the increasing doses of betulin, the inhibition rate of EC109 cell growth was increased, and their morphological characteristics were changed significantly. The inhibition rate showed dose-dependent relation.

Leukemia

Betulin hence showed potent inhibiting effects on EC109 cells growth in vitro (Cai, 2006).

A major compound of the methanolic extract of Dillenia indica L. fruits, betulinic acid, showed significant anti-leukaemic activity in human leukaemic cell lines U937, HL60 and K562 (Kumar, 2009).

Betulinic acid effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. It has been shown that betulinic acid induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, betulinic acid was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. In isolated mitochondria, betulinic acid induced release of both cytochrome c and Smac. Taken together, these results indicated that betulinic acid potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia (Ehrhardt, 2009).

Multiple Myeloma

The effect of betulinic acid on the induction apoptosis of human multiple myeloma RPMI-8226 cell line was investigated. The results showed that within a certain concentration range (0, 5, 10, 15, 20 microg/ml), IC50 of betulinic acid to RPMI-8226 at 24 hours was 10.156+/-0.659 microg/ml, while the IC50 at 48 hours was 5.434+/-0.212 microg/ml, and its inhibiting effect on proliferation of RPMI-8226 showed both a time-and dose-dependent manner.

It is therefore concluded that betulinic acid can induce apoptosis of RPMI-8226 within a certain range of concentration in a time- and dose-dependent manner. This phenomenon may be related to the transcriptional level increase of caspase 3 gene and decrease of bcl-xl. Betulinic acid also affects G1/S in cell-cycle which arrests cells at phase G0/G1 (Cheng, 2009).

Anti-angiogenic Effects, Colorectal Cancer

Betulinic acid isolated from Syzygium campanulatum Korth (Myrtaceae) was found to have anti-angiogenic effects on rat aortic rings, matrigel tube formation, cell proliferation and migration, and expression of vascular endothelial growth factor (VEGF). The anti-tumor effect was studied using a subcutaneous tumor model of HCT 116 colorectal carcinoma cells established in nude mice. Anti-angiogenesis studies showed potent inhibition of microvessels outgrowth in rat aortic rings, and studies on normal and cancer cells did not show any significant cytotoxic effect.

In vivo anti-angiogenic study showed inhibition of new blood vessels in chicken embryo chorioallantoic membrane (CAM), and in vivo anti-tumor study showed significant inhibition of tumor growth due to reduction of intratumor blood vessels and induction of cell death. Collectively, these results indicate betulinic acid as an anti-angiogenic and anti-tumor candidate (Aisha, 2013).

Nasopharyngeal Carcinoma Melanoma, Leukemia, Lung, Colon, Breast,Prostate, Ovarian Cancer

Betulinic acid is an effective and potential anti-cancer chemical derived from plants. Betulinic acid can kill a broad range of tumor cell lines, but has no effect on untransformed cells. The chemical also kills melanoma, leukemia, lung, colon, breast, prostate and ovarian cancer cells via induction of apoptosis, which depends on caspase activation. However, no reports are yet available about the effects of betulinic acid on nasopharyngeal carcinoma (NPC), a widely spread malignancy in the world, especially in East Asia.

In a study, Liu & Luo (2012) showed that betulinic acid can effectively kill CNE2 cells, a cell line derived from NPC. Betulinic acid-induced CNE2 apoptosis was characterized by typical apoptosis hallmarks: caspase activation, DNA fragmentation, and cytochrome c release.

These observations suggest that betulinic acid may serve as a potent and effective anti-cancer agent in NPC treatment. Further exploration of the mechanism of action of betulinic acid could yield novel breakthroughs in anti-cancer drug discovery.

Cervical Carcinoma

Betulinic acid has shown anti-tumor activity in some cell lines in previous studies. Its anti-tumor effect and possible mechanisms were investigated in cervical carcinoma U14 tumor-bearing mice. The results showed that betulinic acid (100 mg/kg and 200 mg/kg) effectively suppressed tumor growth in vivo. Compared with the control group, betulinic acid significantly improved the levels of IL-2 and TNF-alpha in tumor-bearing mice and increased the number of CD4+ lymphocytes subsets, as well as the ratio of CD4+/CD8+ at a dose of 200 mg/kg.

Furthermore, treatment with betulinic acid induced cell apoptosis in a dose-dependent manner in tumor-bearing mice, and inhibited the expression of Bcl-2 and Ki-67 protein while upregulating the expression of caspase-8 protein. The mechanisms by which BetA exerted anti-tumor effects might involve the induction of tumor cell apoptosis. This process is also related to improvement in the body's immune response (Wang, 2012).

Anti-oxidant, Cytotoxic and Immunomodifying Activities

Betulinic acid exerted cytotoxic activity through dose-dependent impairment of viability and mitochondrial activity of rat insulinoma m5F (RINm5F) cells. Decrease of RINm5F viability was mediated by nitric oxide (NO)-induced apoptosis. Betulinic acid also potentiated NO and TNF-α release from macrophages therefore enhancing their cytocidal action. The rosemary extract developed more pronounced anti-oxidant, cytotoxic and immunomodifying activities, probably due to the presence of betulinic acid (Kontogianni, 2013).

Pancreatic Cancer

Lamin B1 is a novel therapeutic target of Betulinic Acid in pancreatic cancer. The role and regulation of lamin B1 (LMNB1) expression in human pancreatic cancer pathogenesis and betulinic acid-based therapy was investigated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Elevation of circulating LMNB1 marker in plasma could detect early stages of HCC patients, with 76% sensitivity and 82% specificity. Lamin B1 is a clinically useful biomarker for early stages of HCC in tumor tissues and plasma (Sun, 2010).

It was found that lamin B1 was significantly down-regulated by BA treatment in pancreatic cancer in both in vitro culture and xenograft models. Overexpression of lamin B1 was pronounced in human pancreatic cancer and increased lamin B1 expression was directly associated with low grade differentiation, increased incidence of distant metastasis and poor prognosis of pancreatic cancer patients.

Furthermore, knockdown of lamin B1 significantly attenuated the proliferation, invasion and tumorigenicity of pancreatic cancer cells. Lamin B1 hence plays an important role in pancreatic cancer pathogenesis and is a novel therapeutic target of betulinic acid treatment (Li, 2013).

Multiple Myeloma, Prostate Cancer

The inhibition of the ubiquitin-proteasome system (UPS) of protein degradation is a valid anti-cancer strategy and has led to the approval of bortezomib for the treatment of multiple myeloma. However, the alternative approach of enhancing the degradation of oncoproteins that are frequently overexpressed in cancers is less developed. Betulinic acid (BA) is a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells, making it an attractive anti-cancer agent.

Results in prostate cancer suggest that BA inhibits multiple deubiquitinases (DUBs), which results in the accumulation of poly-ubiquitinated proteins, decreased levels of oncoproteins, and increased apoptotic cell death. In the TRAMP transgenic mouse model of prostate cancer, treatment with BA (10 mg/kg) inhibited primary tumors, increased apoptosis, decreased angiogenesis and proliferation, and lowered androgen receptor and cyclin D1 protein.

BA treatment also inhibited DUB activity and increased ubiquitinated proteins in TRAMP prostate cancer but had no effect on apoptosis or ubiquitination in normal mouse tissues. Overall, this data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in prostate cancer but not in normal cells and tissues may provide an effective non-toxic and clinically selective agent for chemotherapy (Reiner, 2013).

Melanoma

Betulinic acid was recently described as a melanoma-specific inducer of apoptosis, and it was investigated for its comparable efficacy against metastatic tumors and those in which metastatic ability and 92-kD gelatinase activity had been decreased by introduction of a normal chromosome 6. Human metastatic C8161 melanoma cells showed greater DNA fragmentation and growth arrest and earlier loss of viability in response to betulinic acid than their non-metastatic C8161/neo 6.3 counterpart.

These effects involved induction of p53 without activation of p21WAF1 and were synergized by bromodeoxyuridine in metastatic Mel Juso, with no comparable responses in non-metastatic Mel Juso/neo 6 cells. These data suggest that betulinic acid exerts its inhibitory effect partly by increasing p53 without a comparable effect on p21WAF1 (Rieber, 1998).

As a result of bioassay–guided fractionation, betulinic acid has been identified as a melanoma-specific cytotoxic agent. In follow-up studies conducted with athymic mice carrying human melanomas, tumor growth was completely inhibited without toxicity. As judged by a variety of cellular responses, anti-tumor activity was mediated by the induction of apoptosis. Betulinic acid is inexpensive and available in abundant supply from common natural sources, notably the bark of white birch trees. The compound is currently undergoing preclinical development for the treatment or prevention of malignant melanoma (Pisha, 1995).

Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated. In combination with ionizing radiation the effect of betulinic acid on growth inhibition was additive in colony-forming assays.

Betulinic acid also induced apoptosis in human melanoma cells as demonstrated by Annexin V binding and by the emergence of cells with apoptotic morphology. The growth-inhibitory action of betulinic acid was more pronounced in human melanoma cell lines than in normal human melanocytes.

The properties of betulinic acid make it an interesting candidate, not only as a single agent but also in combination with radiotherapy. It is therefore concluded that the strictly additive mode of growth inhibition in combination with irradiation suggests that the two treatment modalities may function by inducing different cell death pathways or by affecting different target cell populations (Selzer, 2000).

Betulinic acid has been demonstrated to induce programmed cell death with melanoma and certain neuroectodermal tumor cells. It has been demonstrated currently that the treatment of cultured UISO-Mel-1 (human melanoma cells) with betulinic acid leads to the activation of p38 and stress activated protein kinase/c-Jun NH2-terminal kinase (a widely accepted pro-apoptotic mitogen-activated protein kinases (MAPKs)) with no change in the phosphorylation of extracellular signal-regulated kinases (anti-apoptotic MAPK). Moreover, these results support a link between the MAPKs and reactive oxygen species (ROS).

These data provide additional insight in regard to the mechanism by which betulinic acid induces programmed cell death in cultured human melanoma cells, and it likely that similar responses contribute to the anti-tumor effect mediated with human melanoma carried in athymic mice (Tan, 2003).

Glioma

Betulinic acid triggers apoptosis in five human glioma cell lines. Betulinic acid-induced apoptosis requires new protein, but not RNA, synthesis, is independent of p53, and results in p21 protein accumulation in the absence of a cell-cycle arrest. Betulinic acid-induced apoptosis involves the activation of caspases that cleave poly(ADP ribose)polymerase.

Betulinic acid induces the formation of reactive oxygen species that are essential for BA-triggered cell death. The generation of reactive oxygen species is blocked by BCL-2 and requires new protein synthesis but is unaffected by caspase inhibitors, suggesting that betulinic acid toxicity sequentially involves new protein synthesis, formation of reactive oxygen species, and activation of crm-A-insensitive caspases (Wolfgang, 1999).

Head and Neck Carcinoma

In two head and neck squamous carcinoma (HNSCC) cell lines betulinic acid induced apoptosis, which was characterized by a dose-dependent reduction in cell numbers, emergence of apoptotic cells, and an increase in caspase activity. Western blot analysis of the expression of various Bcl-2 family members in betulinic acid–treated cells showed, surprisingly, a suppression of the expression of the pro-apoptotic protein Bax but no changes in Mcl-1 or Bcl-2 expression.

These data clearly demonstrate for the first time that betulinic acid has apoptotic activity against HNSCC cells (Thurnher et al., 2003).

References

Abe F, Yamauchi T, Nagao T, et al. (2002). Ursolic acid as a trypanocidal constituent in rosemary. Biological & Pharmaceutical Bulletin, 25(11):1485–7. doi:10.1248/bpb.25.1485. PMID 12419966.


Aisha AF, Ismail Z, Abu-Salah KM, et al. (2013). Syzygium campanulatum korth methanolic extract inhibits angiogenesis and tumor growth in nude mice. BMC Complement Altern Med,13:168. doi: 10.1186/1472-6882-13-168.


Cai WJ, Ma YQ, Qi YM et al. (2006). Ai bian ji bian tu bian can kao wen xian ge shi    Carcinogenesis,Teratogenesis & Mutagenesis,18(1):16-8.


Cheng YQ, Chen Y, Wu QL, Fang J, Yang LJ. (2009). Zhongguo Shi Yan Xue Ye Xue Za Zhi, 17(5):1224-9.


Chowdhury AR, Mandal S, Mittra B, et al. (2002). Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives. Medical Science Monitor, 8(7): BR254–65. PMID 12118187.


Ehrhardt H, Fulda S, FŸhrer M, Debatin KM & Jeremias I. (2004). Betulinic acid-induced apoptosis in leukemia cells. Leukemia, 18:1406–1412. doi:10.1038/sj.leu.2403406


Gao H, Wu L, Kuroyanagi M, et al. (2003). Anti-tumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells. Chemical & Pharmaceutical Bulletin, 51(11):1318–21. doi:10.1248/cpb.51.1318. PMID 14600382.


Ji ZN, Ye WC, Liu GG, Hsiao WL. (2002). 23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells. Life Sciences, 72(1):1–9. doi:10.1016/S0024-3205(02)02176-8. PMID 12409140.


Kontogianni VG, Tomic G, Nikolic I, et al. (2013). Phytochemical profile of Rosmarinus officinalis and Salvia officinalis extracts and correlation to their anti-oxidant and anti-proliferative activity. Food Chem,136(1):120-9. doi: 10.1016/j.foodchem.2012.07.091.


Kumar D, Mallick S, Vedasiromoni JR, Pal BC. (2010). Anti-leukemic activity of Dillenia indica L. fruit extract and quantification of betulinic acid by HPLC. Phytomedicine, 17(6):431-5.


Li L, Du Y, Kong X, et al. (2013). Lamin B1 Is a Novel Therapeutic Target of Betulinic Acid in Pancreatic Cancer. Clin Cancer Res, Epub July 9. doi: 10.1158/1078-0432.CCR-12-3630


Liu Y, Luo W. (2012). Betulinic acid induces Bax/Bak-independent cytochrome c release in human nasopharyngeal carcinoma cells. Molecules and cells, 33(5):517-524. doi: 10.1007/s10059-012-0022-5


Pisha E, Chai H, Lee I-S, et al. (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nature Medicine, 1:1046 – 1051. doi: 10.1038/nm1095-1046


Pyo JS, Roh SH, Kim DK, et al. (2009). Anti-Cancer Effect of Betulin on a Human Lung Cancer Cell Line: A Pharmacoproteomic Approach Using 2 D SDS PAGE Coupled with Nano-HPLC Tandem Mass Spectrometry. Planta Med, 75(2): 127-131. doi: 10.1055/s-0028-1088366


Reiner T, Parrondo R, de Las Pozas A, Palenzuela D, Perez-Stable C. (2013). Betulinic Acid Selectively Increases Protein Degradation and Enhances Prostate Cancer-Specific Apoptosis: Possible Role for Inhibition of Deubiquitinase Activity. PLoS One, 8(2):e56234. doi: 10.1371/journal.pone.0056234.


Rieber M & Strasberg-Rieber M. (1998). Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma. DNA Cell Biol, 17(5):399–406. doi:10.1089/dna.1998.17.399.


Rzeski W, Stepulak A, Szymanski M, et al. (2009). Betulin Elicits Anti-Cancer Effects in Tumor Primary Cultures and Cell Lines In Vitro. Basic and Clinical Pharmacology and Toxicology, 105(6):425–432. doi: 10.1111/j.1742-7843.2009.00471.x


Selzer E, Pimentel E, Wacheck V, et al. (2000). Effects of Betulinic Acid Alone and in Combination with Irradiation in Human Melanoma Cells. Journal of Investigative Dermatology, 114:935–940; doi:10.1046/j.1523-1747.2000.00972.x


Sun S, Xu MZ, Poon RT, Day PJ, Luk JM. (2010). Circulating Lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J Proteome Res, 9(1):70-8. doi: 10.1021/pr9002118.


Tan YM, Yu R, Pezzuto JM. (2003). Betulinic Acid-induced Programmed Cell Death in Human Melanoma Cells Involves Mitogen-activated Protein Kinase Activation. Clin Cancer Res, 9:2866.


Thurnher D, Turhani D, Pelzmann M, et al. (2003). Betulinic acid: A new cytotoxic compound against malignant head and neck cancer cells. Head & Neck. 25(9):732–740. doi: 10.1002/hed.10231


Wang P, Li Q, Li K, Zhang X, et al. (2012). Betulinic acid exerts immunoregulation and anti-tumor effect on cervical carcinoma (U14) tumor-bearing mice. Pharmazie, 67(8):733-9.


Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M. (1999). Betulinic Acid-Induced Apoptosis in Glioma Cells: A Sequential Requirement for New Protein Synthesis, Formation of Reactive Oxygen Species, and Caspase Processing. JPET, 289(3):1306-1312.


Zuco V, Supino R, Righetti SC, et al. (2002). Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Letters, 175(1): 17–25. doi:10.1016/S0304-3835(01)00718-2. PMID 11734332.

A375 and Hs294, A431, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, anti-oxidant, anti-oxidative, anti-proliferative, anti-proliferative effect, apoptosis, apoptosis induction, Apoptotic, Autophagy, BAX, Bcl-2, Bcl-xL, BCRP/ABCG2, Berberis amurensis, BIU-87 and T24, Breast cancer, Breast cancer cell lines, CDK, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-preventive agent, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, cytotoxic, Diarrhea or Constipation, ER, ER-negative, ER-positive, FAK, G0/G1, G1, growth-inhibitory, hepato-protective, HIF, HL-60, inflammation, Leukemia, Liver cancer, LNCaP, DU145, PC-3, Lymphoma, MCF-7, MCF-7, MDA-MB-231, Melanoma, metastasis, Nitric Oxide, OVCAR-3, SKOV-3, PARP, PC3, PGE2, Pro-apoptotic, Prostate cancer, Radio-sensitizer, radiotherapy, ROS, SiHa and CaSki, Skin cancer, T98G, type, u-PA, VEGF, VEGF

Berberine

Cancer:
Liver,leukemia, breast, prostate, epidermoid (squamous-cell carcinoma), cervical.,testicular, melanoma, lymphoma, hepatoma

Action: Radio-sensitizer, anti-inflammatory, cell-cycle arrest, angiogenesis, chemo-enhancing, anti-metastatic, anti-oxidative

Berberine is a major phytochemical component of the roots and bark of herbal plants such as Berberis, Hydrastis canadensis and Coptis chinensis. It has been implicated in the cytotoxic effects on multiple cancer cell lines.

Anti-inflammatory

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum (Sieb. et Zucc.), a widely prescribed Chinese herb (Chen et al., 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial., anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al., 2001; Yu et al., 2005; Kulkarni & Dhir, 2010; Han et al., 2011; Ji, 2011). Berberine has been used in the treatment of diarrhea, neurasthenia, arrhythmia, diabetes, and so forth (Ji, 2011).

Angiogenesis, Chemo-enhancing

Inhibition of tumor invasion and metastasis is an important aspect of berberine's anti-cancer activities (Tang et al., 2009; Ho et al., 2009). A few studies have reported berberine's inhibition of tumor angiogenesis (Jie et al., 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al., 2008; Hur et al., 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar. 2009; Li et al., 2012). Berberine is also identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al., 2009).

Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al., 2009; Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) (Sun et al., 2009), and caspases (Eom et al., 2010; Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al., 2009; Eom et al., 2010). Interestingly, these effects might be specific for cancer cells (Sun et al., 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumorigenesis and tumor progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al., 2009; Tan et al., 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2 / M phases and by apoptosis (Sun et al., 2009; Eom et al., 2010; Burgeiro et al., 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al., 1990; Eom et al., 2010) and autophagy (Wang et al., 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al., 2009). Besides, berberine also induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al., 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan. (2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012).

Hepatoma, Leukaemia

The cytotoxic effects of Coptis chinensis extracts and their major constituents on hepatoma and leukaemia cells in vitro have been investigated. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were investigated. C. chinensis exhibited strong activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines. These results suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active anti-hepatoma and anti-leukaemia activities (Lin, 2004).

Leukemia

The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 g/ml, 24 to 96 hours) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 over-expressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector–transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 g/ml berberine for 48 to 96 hours.

These results indicate that berberine-induced apoptosis is associated with the down-regulation of nucleophosmin/B23 and telomerase activity. Nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction (Hsing, 1999).

Prostate Cancer

In vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24–72 hours) manner. Berberine significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential., and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.

The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy (Mantena, 2006).

In another study, the treatment of human prostate cancer cells (PC-3) with berberine-induced dose-dependent apoptosis; however, this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential., release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins.

Berberine-induced apoptosis was blocked in the presence of the anti-oxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. Taken together, these results suggest that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer (Meeran, 2008).

Breast Cancer

DNA microarray technology has been used to understand the molecular mechanism underlying the anti-cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells; specifically, whether it affects the expression of cancer-related genes. Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose- and time-dependent manner. The growth-inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells.

IFN-β is among the most important anti-cancer cytokines, and the up-regulation of this gene by berberine is, at least in part, responsible for its anti-proliferative effect. The results of this study implicate berberine as a promising extract for chemoprevention and chemotherapy of certain cancers (Kang, 2005).

Breast Cancer Metastasis

Berberine also inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Anoikis, or detachment-induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localized cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis; however, little is known about the role of berberine in anoikis-resistance.

The anoikis-resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine, which is a drug commonly used to treat breast cancer, in both the adherent and anoikis-resistant cell lines. Berberine promoted the growth inhibition of anoikis-resistant cells to a greater extent than doxorubicine treatment. Treatment with berberine-induced cell-cycle arrest at G0/G1 in the anoikis-resistant MCF-7 and MDA-MB-231 cells was compared to untreated control cells. These results reveal that berberine can efficiently inhibit growth by inducing cell-cycle arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells. Further analysis of these phenotypes is essential for understanding the effect of berberine on anoikis-resistant breast cancer cells, which would be relevant for the therapeutic targeting of breast cancer metastasis (Kim, 2010).

Melanoma

Berberine inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. The effects and associated molecular mechanism of berberine on human melanoma cancer cell migration using melanoma cell lines A375 and Hs294 were probed in an in vitro cell migration assay, indicating that over- expression of cyclo-oxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells.

Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-kB), an up- stream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kB, inhibited cell migration. Together, these results indicate that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors (Sing, 2011).

Cell-cycle Arrest, Squamous-cell Carcinoma

The in vitro treatment of human epidermoid carcinoma A431 cells with berberine decreases cell viability and induces cell death in a dose (5-75 microM)- and time (12–72 hours)-dependent manner, which was associated with an increase in G(1) arrest. G(0)/G(1) phase of the cell-cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins.

Pre-treatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway.

Together, these results indicate berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 (squamous-cell) cells in vitro; further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers (Mantena, 2006).

Cervical Cancer, Radio-sensitizer

Cervical cancer remains one of the major killers amongst women worldwide. In India, a cisplatin based chemo/radiotherapy regimen is used for the treatment of advanced cervical cancer. Evidence shows that most of the chemotherapeutic drugs used in current clinical practice are radio-sensitizers. Natural products open a new avenue for treatment of cancer, as they are generally tolerated at high doses. Animal studies have confirmed the anti-tumorigenic activity of natural products, such as curcumin and berberine.

Berberine is a natural chemo-preventive agent, extracted from Berberis aristata, which has been shown to suppress and retard carcinogenesis by inhibiting inflammation.

The combined therapy of cisplatin/berberine and radiotherapy produced up-regulation of pro-apoptotic proteins Bax and p73, while causing down regulation of the anti-apoptotic proteins Bcl-xL, COX-2, cyclin D1. This additionally was accompanied by increased activity of caspase-9 and caspase-3, and reduction in telomerase activity. Results demonstrated that the treatment combination of berberine/cisplatin had increased induction of apoptosis relative to cisplatin alone (Komal., Singh, & Deshwal., 2013).

Anti-oxidative; Breast, Liver and Colon Cancer

The effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation (lipid peroxidation), diphenyle–alpha-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and alpha-gulcosidase activities were spectrophotometrically determined.

Barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent anti-oxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that is associated with GPx and SOD hyperactivation. Both berberine chloride and barberry ethanolic extract were shown to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (MCF7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hours up to 72 hours and the inhibitory effect increased with time in a dose-dependent manner.

This work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, for suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. As well, berberis vulgaris ethanolic extract is a safe non-toxic extract as it does not inhibit the growth of PBMC that can induce cancer cell death (Abeer et al., 2013).

Source:

Alkaloids Isolated from Natural Herbs as the Anti-cancer Agents. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/485042

References

Burgeiro A, Gajate C, Dakir EH, et al. (2011). Involvement of mitochondrial and B-RAF/ERK signaling pathways in berberine-induced apoptosis in human melanoma cells. Anti-Cancer Drugs, 22(6):507–518.


Chang KSS, Gao C, Wang LC. (1990). Berberine-induced morphologic differentiation and down-regulation of c-Ki-ras2 protooncogene expression in human teratocarcinoma cells. Cancer Letters, 55(2):103–108.


Chen J, ZHao H, Wang X, et al. (2008). Analysis of major alkaloids in Rhizoma coptidis by capillary electrophoresis-electrospray-time of flight mass spectrometry with different background electrolytes. Electrophoresis, 29(10):2135–2147.


Eom KS, Kim HJ, So HS, et al. (2010). Berberine-induced apoptosis in human glioblastoma T98G Cells Is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction. Biological and Pharmaceutical Bulletin, 33(10):1644–1649.


El-Wahab AEA, Ghareeb DA, et al. (2013). In vitro biological assessment of berberis vulgaris and its active constituent, berberine: anti-oxidants, anti-acetylcholinesterase, anti-diabetic and anti-cancer effects. BMC Complementary and Alternative Medicine, 13:218 doi:10.1186/1472-6882-13-218


Hamsa TP & Kuttan G. (2011). Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells. Phytotherapy Research, 26(4):568–578.


Hamsa TP & Kuttan G. (2012). Anti-angiogenic activity of berberine is mediated through the down-regulation of hypoxia-inducible factor-1, VEGF, and pro-inflammatory mediators. Drug and Chemical Toxicology, 35(1):57–70.


Han J, Lin H, Huang W. (2011). Modulating gut microbiota as an anti-diabetic mechanism of berberine. Medical Science Monitor, 17(7):RA164–RA167.


Ho YT, Yang JS, Li TC, et al. (2009). Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9. Cancer Letters, 279(2):155–162.


Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. (2009). The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. Journal of Cellular Biochemistry, 107(5):955–964.


Islam MM & Kumar GS. (2009). RNA-binding potential of protoberberine alkaloids: spectroscopic and calorimetric studies on the binding of berberine, palmatine, and coralyne to protonated RNA structures. DNA and Cell Biology, 28(12):637–650.


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


Jie S, Li H, Tian Y, et al. (2011). Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. Journal of Gastroenterology and Hepatology, 26(1):179–185.


Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-regulation of interferon-β and TNF-α in human breast cancer cells. Carcinogenesis, 26(11):1934-1939. doi:10.1093/carcin/bgi154


Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Phytomedicine, 17(6):436-40. doi: 10.1016/j.phymed.2009.08.012.


Komal Singh M, & Deshwal VK. (2013). Natural plant product berberine/cisplatin based radiotherapy for cervical cancer: The new and effective method to treat cervical cancer. Global Journal of Research on Medicinal Plants and Indigenous Medicine, 2(5), 278-291.


Kulkarni SK & Dhir A. (2010). Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytotherapy Research, 24(3):317–324.


Lau CW, X. Q. Yao XQ, et al. (2001). Cardiovascular actions of berberine. Cardiovascular Drug Reviews, 19(3):234–244.


Li, XL Hu XJ, Wang H, et al. (2012). Molecular spectroscopy evidence for berberine binding to DNA: comparative binding and thermodynamic profile of intercalation. Biomacromolecules, 13(3):873–880.


Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC. (2004). Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin Exp Pharmacol Physiol, 31(1-2):65-9.


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine, a natural product, induces G1-phase cell-cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther, 5(2):296-308. doi: 10.1158/1535-7163.MCT-05-0448


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 27(10):2018-27. doi: 10.1093/carcin/bgl043


Meeran SM, Katiyar S & Katiyar SK. (2008). Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicology and Applied Pharmacology, 229(1):33-43. doi:10.1016/j.taap.2007.12.027


Singh T, Vaid M, Katiyar N, et al. (2011). Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E and prostaglandin E receptors. Carcinogenesis, 32(1):86–92.


Sun Y, Xun K, Wang Y, Chen X. (2009). A systematic review of the anti-cancer properties of berberine, a natural product from Chinese herbs. Anti-Cancer Drugs, 20(9):757–769.


Tan W, Lu J, Huang M, et al. (2011). Anti-cancer natural products isolated from chinese medicinal herbs. Chinese Medicine, 6(1):27.


Tang F, Wang D, Duan C, et al. (2009) Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting rho kinase-mediated ezrin phosphorylation at threonine 567. Journal of Biological Chemistry, 284(40):27456–27466.


Wang N, Feng Y, Zhu M et al. (2010). Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. Journal of Cellular Biochemistry, 111(6):1426–1436.


Wu HL, Hsu CY, Liu WH, Yung BYM. (1999). Berberine‐induced apoptosis of human leukemia HL‐60 cells is associated with down‐regulation of nucleophosmin/B23 and telomerase activity. International Journal of Cancer, 81(6):923–929.


Youn MJ, So HS, Cho HJ, et al. (2008). Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biological and Pharmaceutical Bulletin, 31(5):789–795.


Yu HH, Kim KJ, Cha JD, et al. (2005). Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Journal of Medicinal Food, 8(4):454–461.

Akt, Alismatis Rhizoma, anti-proliferative, anti-proliferative effect, apoptosis, B16F10, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, Cytostatic, cytotoxic, Gastric cancer or Stomach cancer, Hep3B, HepG2-DR, HT1080, K562-DR, Melanoma, p-Akt, PC3, PI3K, PI3K/Akt, Sarcoma, SGC7901, SKOV3

Alisol B Acetate

Cancer:
Liver, melanoma, ovarian, sarcoma, gastric cancer

Action: Cytostatic, cytotoxic

Four prostane-type triterpenes were isolated from a methanol extract of Alismatis Rhizoma by bioassay-guided isolation using in vitro cytotoxic assay. The compounds were identified as alisol B 23-acetate (1), alisol C 23-acetate (2), alisol B (3), alisol A 24-acetate (4) by spectroscopic methods. Amongst the compounds, alisol B (3) showed significant cytotoxicity against SK-OV3, B16-F10, and HT1080 cancer cell lines with ED50 values of 7.5, 7.5, 4.9 microg/ml, respectively (Lee et al., 2001).

Hepatocellular Carcinoma

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

Results suggest that alisol B acetate and saikosaponin-d induced cell apoptosis through the caspase-3-dependent and -independent pathways, respectively. Instead of inducing apoptosis, baicalein inhibits TGF-beta(1)-induced apoptosis via increase in cellular H(2)O(2) formation and NF-kappaB activation in human hepatoma Hep3B cells (Chou, Pan, Teng & Guh, 2003).

Gastric Cancer

The cytotoxic effect of alisol B acetate on SGC7901 cells was measured by MTT assay and phase-contrast and electron microscopy. Cell-cycle and mitochondrial transmembrane potential (Deltapsim) were determined by flow cytometry and Western blotting was used to detect the expression of apoptosis-regulated gene Bcl-2, Bax, Apaf-1, caspase-3, caspase-9, Akt, P-Akt and phosphatidylinositol 3-kinases (PI3K).

Alisol B acetate inhibited the proliferation of SGC7901 cell line in a time- and dose-dependent manner. Alisol B acetate exhibits an anti-proliferative effect in SGC7901 cells by inducing apoptosis. Apoptosis of SGC7901 cells involves mitochondria-caspase and PI3K/Akt dependent pathways (Xu, Zhao & Li, 2009).

References

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

 

 

Lee S, Kho Y, Min B, et al. (2001). Cytotoxic triterpenoides from Alismatis rhizome. Archives of Pharmacal Research. 24(6), 524-526.

 

Xu YH, Zhao LJ, & Li Y. (2009). Alisol B acetate induces apoptosis of SGC7901 cells via mitochondrial and phosphatidylinositol 3-kinases/Akt signaling pathways.

 

World Journal of Gastroenterology, 15(23), 2870-2877.

Anti-cancer, Anti-cancer effect, anti-proliferative, Apoptotic, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, cytotoxic, Fissistigma glaucescens, Gastric cancer or Stomach cancer, Liver cancer, Lung cancer, metastasis, Ovarian cancer, PAK1, Pro-apoptotic, radiotherapy

Xiao Ai Ping

Cancer: Lung, gastric, ovarian, liver

Action: Anti-proliferative, chemo-sensitizer, pro-apoptotic

Ingredients: wu gu teng (Fissistigma glaucescens)

TCM functions: Clearing Heat, removing Toxin, dissolving Phlegm and softening the hardness.

Indications: Esophagus cancer, stomach cancer, lung cancer, ovarian cancer and liver cancer.

Dosage and usage:

Intravenous drip: 20-100ml mixed with 5% or 10% glucose injection, once daily.

Xiaoaiping Injection (XAP) is made from extracts from wu gu teng (Fissistigma glaucescens). Its TCM functions are Clearing Heat, removing Toxin, dissolving Phlegm and softening the hardness. It is used in the treatment of esophagus cancer, stomach cancer, lung cancer and liver cancer. It can be used as an adjuvant therapy for radiotherapy or chemotherapy (Drug Information Reference in Chinese: See end, 2006).

Lung Cancer

Lewis lung cancer (LLC) bearing mice were injected intraperitoneally daily with various doses of cisplatin, Xiao-Ai-Ping, or cisplatin plus Xiao-Ai-Ping, respectively. The combination of Xiao-Ai-Ping and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than sole drug treatment did. In addition, Xiao-Ai-Ping triggered the infiltration of CD8+ T cells, a group of cytotoxic T cells, to LLC xenografts. In vitro studies showed that Xiao-Ai-Ping markedly upregulated the mRNA levels of ifn-?, prf-1, and gzmb in CD8+ T cells in a concentration-dependent manner, suggesting that Xiao-Ai-Ping augments the function of CD8+ T cells.

Xiao-Ai-Ping promotes the infiltration and function of CD8+ T cells and thus enhances the anti-growth effects of cisplatin on LLC xenografts, which provides new evidence for the combination of Xiao-Ai-Ping and cisplatin in clinic in China (Li et al., 2013).

Hepatocellular Carcinoma

Xiao-Ai-Ping (XAP) enhances the quality of life (QOL) of patients with advanced HCC, improves their immunity and extends their PFS. XAP was administered daily by i.v. and the treatment course lasted for 30 days for both groups. The progression-free survival (PFS) rate and overall survival (OS) rate in the 2 groups were analyzed. The 6-months cumulative survival rates in the treatment and control groups were 33.3% and 25.0%, respectively, with no significant difference (P > 0.05). The PFS was 18 weeks in the treatment group and 15 weeks in control group (P < 0.05) (Huang et al., 2013).

NSCLC

Seventy nine patients with terminal NSCLC patients were divided into the control group and the treatment group. The control group: paclitaxel 135 mg/m2,the 1st day intravenous drip, cisplatin 30 mg/m2, the 1st day ~ 3rd day, intravenous drip (TP regimen). The treatment group: Xiaoaiping injection combined with TP regimen. The clinical data of two groups was compared.

The short-term  curative effect and quality of life in the treatment group was better than the control group. The adverse effect of treatment group was slightly lower. Xiaoaiping injection in combination with TP regimen in the treatment of non-small-cell lung cancer has better efficacy, effectively improves the clinical symptoms and improves quality of life with fewer adverse reactions (Guoan, 2013).

Gastric Cancer

To investigate the effect and toxicities of xiaoaiping injection in the treatment of the elderly patients with advanced gastric carcinoma, forty-six elderly patients with advanced gastric carcinoma in the test group were treated with xiaoaiping injection plus supportive care, and the 30 patients of the control group were treated with supportive care alone. The total effective rate, the excellence plus effectiveness rate and the improvement rate of quality of life of the test group were better than those of the control group (P<0.05). Xiaoaiping injection is effective and safe in the treatment of the elderly patients with advanced gastric carcinoma (Liu et al., 2012).

Ovarian Cancer; Metastasis

The ovarian cancer Caov-3 cells were treated with xiaoaiping (XAP) in vitro. The inhibitor doxycyclin was also applied to the metalloproteinase-9 (MMP) as the positive control, whereas phosphate-buffered saline served as the negative control. XAP effectively inhibited Caov-3 cell migration and invasion and decreased the MMP-9 gene and protein expression levels (P<0.05). Moreover, the inhibitory effect of XAP was similar to that of doxycyclin (P>0.05). Conclusion: XAP inhibits Caov-3 cell migration by decreasing the MMP-9 expression (Wang et al., 2012).

Hepatoma

Zhao at al. (2011) researched the inhibitory effect of the combination of octreotide acetate and Xiaoaiping injection on hepatoma Hepal-6 cells and the expression of PAK1 protein. The different concentrations (10, 30, 50mg/ml), the different times (-24, -16, -8, 0 hours, 8, 16 & 24 hours), and the inhibition of the combination of oetreotide acetate and Xiaoaiping injection on Hepal-6 cells were detected by MTT assay.

Xiaoaiping of 50mg/ml combined with octreotide acetate was the best concentration of pharmacodynamie action for treating liver cancer (P<0. 05). Xiaoaiping of 50mg/nd combined with octreotide acetate was the best concentration for anti-cancer effect. Using oetreotide acetate 8 hours early was the best time for anti-cancer treatment, and its motility decreased significantly. Above all, down-regulating the PAK1 protein could restrain the proliferation of tumors and reduce motility. This provided the theoretical basis in targeted treatment for hepatocellular carcinoma.

References

Guoan X. (2013). Effect of xiaoaiping injection combined with TP regimen in the treatment of advanced non-small-cell lung cancer. Lin Chuang Yi Yao Shi Jian, 22(2): 83-85.


Huang, Z., Wang, Y., Chen, J., Wang, R., Chen, Q. (2013) Effect of Xiaoaiping injection on advanced hepatocellular carcinoma in patients. J Tradit Chin Med, 33(1):34-8.


Li, W.S., Yang, Y., Ouyang, Z.J. (2013). Xiao-Ai-Ping, a TCM injection, enhances the anti-growth effects of cisplatin on Lewis lung cancer cells through promoting the infiltration and function of CD8+ T lymphocytes. Evidence-Based Complementary and Alternative Medicine, 2013(2013):879512. doi:10.1155/2013/879512.


Liu X, Su Q, Mao X, Xue L, et al. (2012). Effect of Xiaoaiping Injection in the Treatment of the Elderly Patients with Advanced Gastric Carcinoma. Zhong Liu Ji Chu Yu Lin Chuang, 15(6): 513-514.


Wang. C., Dong, X., Wang, M., Wang, X. (2012). Xiaoaiping Injection Inhibits Cell Migration by Reducing MMP-9 Gene Expression in Human Ovarian Cancer Cells. Zhong Guo Zhong Liu Lin Chuang, 29(13): 886-888.


Xiao G. (2013). Effect of xiaoaiping injection combined with TP regimen in the treatment of advanced non-small-cell lung cancer. Lin Chuang Yi Yao Shi Jian, 22(2): 83-85.


Zhao HP, Liang LQ, Xie YR. (2011). Growth inhibition effect of Xiaoaiping injection combined with octreotide acetate on Hepal-6 cells and the expression of PAK1. Lin Chuang Zhong Liu Xue Za Zhi, 16(1): 19-22.

Anti-cancer, anti-tumor, anti-tumor immunity, apoptosis, Breast cancer, Breast cancer cell lines, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, Damages DNA, G2/M, Pancreatic cancer

Ukrain

Cancer: Breast, pancreatic, bladder, colorectal

Action: Damages DNA

Ukrain has been described as a semi-synthetic Chelidonium majus alkaloid derivative, consisting of three chelidonine alkaloids combined to triaziridide. Panzer et al. (2000) found the actions of Ukrain to be similar to the Chelidonium majus alkaloids from which it is prepared. Chelidonium majus contains a range of more than 30 alkaloids, most notably isochinolin derivatives (chelidonine, coptisine, berberin etc.). Chemical analyzes of Ukrain were inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine) (Panzer et al., 2000).

Ukrain was developed in 1978 by Dr. Wassil J. Nowicky, director of the Ukrainian Anti-Cancer Institute of Vienna, Austria, and was first presented at the 13th International Congress of Chemotherapy in Vienna in August 1983. In 2004 and 2006, Nowicky was nominated for the Nobel Prize in Chemistry. The manufacturer of Ukrain is Nowicky Pharma, A-1040 Vienna, Austria.

Several reports describe Eastern European clinical trials using Ukrain for people with various types of cancer (Susak et al., 1996). The mechanism of action of Ukrain is unknown whereas the mechanism of action of thiotepa is known. The drug works by damaging the DNA of cells, leaving the cell unable to divide.

The proposed activity of Ukrain includes cytotoxicity from effects on cellular oxygen consumption, inhibition of DNA, RNA, and protein synthesis, and induction of apoptosis. In vitro studies demonstrate weak inhibition of tubulin polymerization causing arrest at G2/M phase of the cell-cycle. Limited in vitro data support the claim that Ukrain has selective cytotoxicity against cancer cells. Ukrain also is promoted for its claimed ability to increase total T-cell count and T-helper lymphocytes, while decreasing T-suppressor cells. In vitro activation of splenic lymphocytes also was reported (Colombo et al., 1996; Panzer et al., 2000; Uglyanitsa et al., 1998).

Ukrain has no drug approval in the EU. In the UK, Ukrain neither hasmarketing authorization nor is it registered under the “traditional use” label. It is not FDA-approved in the US but is approved in Mexico, and in the United Arab Emirates, as a standard anti-cancer medication. According to the manufacturer, NSC 631570 (=Ukrain) has drug licences in several states of the former Soviet Union (Ukraine, Georgia, Turkmenistan, Belarus/White Russia, Azerbaijan Republic, Tadshikistan, and the Ukraine. They also claim, without validation, that Ukrain has also been designated as an Orphan Drug for pancreatic cancer in the USA and in Australia (Human life Science Holding, n.d.).

There are seven RCTs assessing the efficacy of Ukrain for various cancer types (Ernst & Schmidt, 2005). The majority of these studies were published in two different journals between 1995 and 2002 by four different groups of authors, three from  Belarus and one from Germany. They relate to colorectal (Susak et al., 1995; Susak et al., 1996) rectal (Bondar et al., 1998), bladder (Uglyanitsa et al., 1998), pancreatic (Zemskov et al., 2000; Zemskov et al., 2002), and breast cancers (Uglyanitsa et al., 2000). Ukrain exposure induced apoptosis in a dose- and time-dependent manner with 50 µg/mL Ukrain leading to >50% cell death after 48 hour exposure for all three breast cancer cell lines.

Ukrain administration (12.5 mg/kg) led to significant inhibition of 4T07 tumor growth in vivo and sustained protective anti-tumor immunity following secondary challenge. Findings demonstrate the in vitro and in vivo cytotoxic effects of Ukrain on breast cancer cells and may provide insight into designing Ukrain-based therapies for breast cancer patients (Bozeman et al., 2012).

While common anti-cancer drugs are toxic both against cancer and normal cells (cytostatics), Ukrain is allegedly only toxic against cancer cells (“malignocytolytic”). Some studies suggest that there was no evidence to suggest selective cytotoxicity previously reported for Ukrain (Panzer et al., 2000). Research carried out at the National Cancer Institute where Ukrain was tested on the screening panel with 60 cell lines from eight human cancer types, it was revealed to be cytotoxic against all the solid cancer cell lines tested (Boehm & Ernst, 2013).

References

Boehm, K., Ernst, E. (2013) CAM-Cancer Consortium. Ukrain [online document]. http://cam-cancer.org/CAM-Summaries/Herbal-products/Ukrain. August 21, 2013.


Bondar, G.V., Borota, A.V., Yakovets, Y.I., Zolotukhin, S.E.(1998)  Comparative evaluation of the complex treatment of rectal cancer patients (chemotherapy and X-ray therapy, Ukrain monotherapy). Drugs Exp Clin Res 1998;24:221-6.

Bozeman, E.N., Srivatsan, S., Mohammadi, H., et al. (2012) Ukrain, a plant derived semi-synthetic compound, exerts anti-tumor effects against murine and human breast cancer and induce protective anti-tumor immunity in mice.  Exp Oncol. 2012 Dec;34(4):340-7.


Colombo, M.L., Bosisio, E.. (1996) Pharmacological activities of Chelidonium majus L. (papaveracea). Pharmacol Res 1996;33:127-34.


Ernst, E., Schmidt, K. (2005) Ukrain – a new cancer cure? A systematic review of randomised clinical trials. BMC Cancer 2005;5:69-75.


Human life Science Holding. (n.d) http://www.open-cc.com/English/1_04.asp Accessed 2 December 2013


Panzer, A., Hamel, E., Joubert, A.M., Bianchi, P.C., Seegers, J.C.. (2000) Ukrain (TM), a semisynthetic Chelidonium majus alkaloid derivative, acts by inhibition of tubulin polymerization in normal and malignant cell lines. Cancer Lett 2000;160(2):149-57.


Susak, Y.M., Yaremchuk, O.Y., Zemskov, V.S., Kravchenko, O.B., et al. (1995) Randomised clinical study of Ukrain on colorectal cancer. Eur J Cancer 1995;31:S153 Abstract 733.


Susak, Y.M., Zemskov, V.S., Yaremchuk, O.Y., et al. (1996) Comparison of chemotherapy and x-ray therapy with Ukrain monotherapy for colorectal cancer. Drugs Exptl Clin Res 1996;22:115–22.


Uglyanitsa, K.N., Nechiporenko, N.A., Nefyodov, L.I., Brzosko, W.J. (1998) Ukrain therapy of stage T1NOMO bladder cancer patients. Drugs Exp Clin Res 1998;24:227-30.

anti-apoptotic, anti-inflammatory, Antibiotic, apoptosis, Apoptotic, Chapter 8 Injectables and Cancer Research, cytotoxic, Fibrosarcoma, Leukemia, neuro-protective, Pro-apoptotic, Sarcoma

Qingkailing

Cancer: Leukemia, sarcoma

Action: Antibiotic, anti-apoptotic, anti-inflammatory, neuro-protective, pro-apoptotic, immunomodulating, MMPs regulation

Anti-inflammatory and Immunomodulating

Qingkailing and Shuanghuanglian (SHHL) are two commonly used Chinese herbal preparations with reported anti-inflammatory activity. The effects of these two preparations on the capacity of staphylococcal toxic shock syndrome toxin 1 (TSST-1), to stimulate the production of cytokines (IL-1β, IL-6, TNF-α, IFN-γ) and chemokines (MIP-1α, MIP-1β and MCP-1) by peripheral blood mononuclear cell (PBMC), was tested. Their effect on LPS-stimulated NF-κB transcriptional activity in a THP-1 cell line, and on human monocyte chemotactic response to chemoattractants, was also evaluated.

The results suggested that the pharmacological basis for the anti-inflammatory effects of Qingkailing and SHHL is the result of suppression of NF-κB regulated gene transcription, leading to suppressed production of pro-inflammatory cytokines and chemokines. Interference with leukocyte chemotaxis also contributes to the anti-inflammatory and immunomodulating effects of these medicinals. Identification of the responsible components in these two herbal preparations may yield compounds suitable for structural modification into potent novel drugs (Chen et al., 2002).

Leukemia

The MTT assay, cell morphology, DNA gel electrophoresis, and flow-cytometry were utilized to study the apoptotic effect of Qingkailing, and its active compounds, on the human acute promyelocytic leukemia (HL-60) cell line.

Qingkailing and its active compounds, Baicalin and hyodeoxycholic acid, exhibited strong cytotoxicity in inhibiting HL-60 cells, while Bezoar cholic acid showed a weaker effect. Apoptosis could be induced after being treated for 6 h by the former two compounds, displaying a typical apoptosis peak under flow-cytometry, but could not be induced by the latter.

Qingkailing could induce apoptosis in leukemia cells in vitro, which could serve as a mechanism of Qingkailing in the treatment of acute promyelocytic leukemia (Chen, Dong, & Zhang, 2001).

Qingkailing injection could prevent the decrease of MMP induced by injury of hypoxia-hypoglycemia-reoxygenation, stabilize MMP, inhibit cell apoptosis, and protect hippocampal neurons (Tsing, 2006).

Matrix Metalloproteinases (MMPs) Regulation

Matrix metalloproteinases (MMPs) play vital roles in many pathological conditions, including cancer, cardiovascular disease, arthritis and inflammation. Modulating MMP activity may therefore be a useful therapeutic approach in treating these diseases. Qingkailing is a popular Chinese anti-inflammatory formulation used to treat symptoms such as rheumatoid arthritis, acute hypertensive cerebral hemorrhage, hepatitis and upper respiratory tract infection.

One of the components of Qingkailing, Fructus gardeniae, strongly inhibits MMP activity. The IC50 values for the primary herbal extract and water extract against MMP-16 were 32 and 27 µg/ml, respectively. In addition, the herbal extracts influenced HT1080 human fibrosarcoma cell growth and morphology.

These data may provide molecular mechanisms for the therapeutic effects of Qingkailing and herbal medicinal Fructus gardenia (Yang et al., 2008).

Sources

Chen X, Howard OM, Yang X, Wang L, Oppenheim JJ, Krakauer T. (2002). Effects of Shuanghuanglian and Qingkailing, two multi-components of traditional Chinese medicinal preparations, on human leukocyte function. Life Sciences, 70(24), 2897-2913.


Chen ZT, Dong Q, Zhang L. (2001). Study on the effect of Qingkailing injection and its active principle in inducing cell apoptosis in human acute promyelocytic leukemia. Chinese Journal of Integrated Traditional and Western Medicine, 21(11), 840-842.


Tsing H. (2006). Influences of Qingkailing Injection on neuron apoptosis and mitochondrial membrane potential. Journal of Beijing University of Traditional Chinese Medicine, 2006(2), R285.5.


Yang JG, Shen YH, Hong Y, Jin FH, Zhao SH, Wang MC, Shi XJ,   Fang XX. (2008). Stir-baked Fructus gardeniae (L.) extracts inhibit matrix metalloproteinases and alter cell morphology. Journal of Ethnopharmacology, 117(2), 285-289.

anti-tumor, Chapter 8 Injectables and Cancer Research, cytotoxic, Immunomodulatory

Pseudostellaria heterophylla

A mitogenic fraction (PH-I) separated from Pseudostellaria heterophylla exhibits both immunomodulatory and anti-tumor activities. It was found that fraction PH-I C from P. heterophylla could markedly suppress the growth of EAT cells in vivo. Mechanistic studies have shown that i.p. injection of PH-I C into mice could enhance the phagocytic activity of thioglycollate-elicited peritoneal macrophages.

Moreover, PH-I C showed a potent activating effect on the cytotoxic activity of natural killer (NK) cells and alloreactive cytotoxic T cells (Tc) as well as increased the MurIL-2-induced lymphokine activated killer cell (LAK) activity in vitro. In addition, PH-I C could increase the number of tumor infiltrating lymphocytes (TILs) in the tumor site of WEHI-164-bearing mice. Finally, i.v. injection of PH-I C significantly elevated the levels of IFN-gamma and IL-4 in sera of EAT-bearing mice (Wong et al., 1994).

References

Wong CK, Leung KN, Fung KP, Choy YM. (1994). The immunostimulating activities of anti-tumor polysaccharides from Pseudostellaria heterophylla. Immunopharmacology, 28(1):47-54.

anti-tumor, anti-tumor activity, Chapter 7 Isolates and Cancer Research, cytotoxic, Enhances phagocytic activity, Immunomodulatory

Pseudostellaria heterophylla

Cancer: none noted

Action: Enhances phagocytic activity

A mitogenic fraction (PH-I) separated from Pseudostellaria heterophylla exhibits both immunomodulatory and anti-tumor activities. PH-I was further purified by gel filtration chromatography and the resulting three fractions (PH-I A, PH-I B and PH-I C) were assessed for their anti-tumor activity in vivo. It was found that fraction PH-I C from P. heterophylla could markedly suppress the growth of EAT cells in vivo. Mechanistic studies have shown that i.p. injection of PH-I C into mice could enhance the phagocytic activity of thioglycollate-elicited peritoneal macrophages.

Moreover, PH-I C showed a potent activating effect on the cytotoxic activity of natural killer (NK) cells and alloreactive cytotoxic T cells (Tc) as well as increased the MurIL-2-induced lymphokine activated killer cell (LAK) activity in vitro. In addition, PH-I C could increase the number of tumor infiltrating lymphocytes (TILs) in the tumor site of WEHI-164-bearing mice. Finally, i.v. injection of PH-I C significantly elevated the levels of IFN-gamma and IL-4 in sera of EAT-bearing mice (Wong et al., 1994).

Reference

Wong CK, Leung KN, Fung KP, Choy YM. (1994). The immunostimulating activities of anti-tumor polysaccharides from Pseudostellaria heterophylla. Immunopharmacology, 28(1):47-54.

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

Artesunate

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

Action: Anti-metastatic, MDR, radio-sensitizer

Pulmonary Adenocarcinomas

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

Breast Cancer

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

Skin Cancer

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

Colon Cancer

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

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

Multi-drug resistance; Colon Cancer

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

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

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

Multi-drug resistance; Esophageal Cancer

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

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

Pancreatic Cancer

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

Ovarian Cancer

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

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

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

Multiple Myeloma, B-cell Lymphoma

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

Osteosarcoma, Leukemia/Lymphoma

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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

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

Multi-drug resistance

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

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

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

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

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

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

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

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

Saponins

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

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

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

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

Flavonoids

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

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

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

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

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

Other Compounds

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

Formulae – injections (See Injectables)

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

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

Formulae – powders

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

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

Formulae – others

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

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

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

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

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

Formulae

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

anti-tumor, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemotherapy, cytotoxic, Fatigue, Immune, immunomodular, inflammation, Nausea and Vomiting, Th1, TNF

LCS101

Cancer: Breast

Action: Chemotherapy, immunomodular

Breast Cancer

Samuels, Maimon, and Zisk-Rony, (2013) treated a series of 20 female breast cancer patients with the botanical compound LCS101 as adjuvant to conventional chemotherapy. At the end of the treatment regimen, patients rated their symptoms. Seventy percent reported that they had either no or mildly severe levels of fatigue; 60% none to mildly severe weakness; 85% none to mildly severe pain; 70% none to mildly severe nausea; and 80% none to mildly severe vomiting. Only 20% reported severe impairment of overall function, and only 40% severely impaired QOL. No toxic effects were attributed by patients to the LCS101 treatment, and 85% reported that they believed the botanical compound had helped reduce symptoms.

Immunomodular

NK cells are considered to be a central mediator in the 'cross talk' between the adaptive and the innate immune systems, and play an important role in the inhibition and killing of tumor cells (Lee & Gasser, 2010). The LCS101 component Astragalus membranaceus has been shown to stimulate NK-cell activity in human peripheral lymphocytes, as well as restoring steroid-inhibited NK-cell activity (Mills & Bone, 2000). Polysaccharides of this herb were shown to enhance NK cell activity of normal subjects and patients with systemic lupus erythematosus. LCS101 was also shown to enhance cytokine production, increasing TNF-α secretion from murine macrophages 100-fold when compared to untreated controls. TNF-α is a potent anti-tumor cytokine that enhances the activity of macrophages, NK cells, and cytotoxic T cells.

Finally, LCS101 was observed to increase production of IFN-γ, correcting decreased levels following 5-FU treatment, and increasing unaltered levels of the cytokine following exposure to doxorubicin. IFN-γ production is induced by T cells, NK cells, and macrophages, and plays a role in the inhibition of tumor growth, promotion of Th1 immune responses, and differentiation of cytotoxic NK and T cells. Immune-competent mice who lack IFN-γ fail to normalize tissue homeostasis and clear low-level microbial infections, resulting in chronic inflammation with an increased incidence of hematological and solid-tissue cancers (Rachmut et al., 2013).

Induced Hematological Toxicities

Sixty-five breast cancer patients were recruited, with 34 allocated to LCS101 and 31 allocated to placebo treatment. Patients in the treatment group developed significantly less severe (grades 2-4) anemia (p < .01) and leukopenia (p < .03) when comparing grades 0-1 with grades 2-4, with significantly less neutropenia (p < .04) when comparing grades 0-2 with grades 3-4. This effect was more significant among patients undergoing a dose-dense regimen. The addition of LCS101 to anthracycline- and taxane-based chemotherapy is safe and well-tolerated, and may significantly prevent some chemotherapy-induced hematological toxicities in early breast cancer patients (Yaal-Hahoshen et al., 2011).

LCS101 Formula:

Astragalus membranaceus, Poriae cocos, Atractylodes macrocephala, Lycium chinense, Ligustrum lucidum, Paeonia lactiflora, Paeonia obovata, Citrus reticulata, Ophiopogon japonicus, Milletia reticulata, Oldenlandia diffusa, Scutellaria barbata, Prunella vulgaris, and Glehnia littoralis.

References

Rachmut IH, Samuels N, Melnick SJ, et al. (2013). Immunomodulatory effects of the botanical compound LCS101: implications for cancer treatment. Onco Targets Ther, 6:437–445. doi:10.2147/OTT.S42038.


Samuels N, Maimon Y, Zisk-Rony RY. (2013). Effect of the Botanical Compound LCS101 on Chemotherapy-Induced Symptoms in Patients with Breast Cancer: A Case Series Report. Integr Med Insights, 8:1–8. doi: 10.4137/IMI.S10841.


Yaal-Hahoshen N, Maimon Y, Siegelmann-Danieli N, et al. (2011). A prospective, controlled study of the botanical compound mixture LCS101 for chemotherapy-induced hematological complications in breast cancer. Oncologist, 16(9):1197-202. doi: 10.1634/theoncologist.2011-0150.

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

Baicalin & Baicalein

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

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

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

Anti-cancer

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

Multiple Myeloma

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

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

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

Hepatoma

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

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

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

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

Ovarian Cancer

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

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

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

Breast Cancer

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

Breast Cancer, Cell Invasion

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

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

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

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

Oral Cancer

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

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

Anti-inflammatory

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

Angiogenesis Modulation

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

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

Colon Cancer

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

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

Cardio-protective

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

Prostate Cancer

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

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

Cancer: Acute lymphocytic leukemia, lymphoma and myeloma

Action: Cell-cycle arrest, induces apoptosis

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

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

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

Emodin (See also Aloe-Emodin)

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

Action: MDR-1, cell-cycle arrest

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

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

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

Pancreatic Cancer

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

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

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

Hepatocellular Carcinoma

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

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

Colon Cancer

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

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

Myeloid Leukemia

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

Breast Cancer; Block HER-2

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

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

MDR

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

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

Cell-cycle Arrest

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

Cell-cycle Arrest; MDR1 & AZT

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

References

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


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


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


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


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


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


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


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


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


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


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

Anti-cancer, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, cytotoxic, MDR

Cnidiadin

Cancer: none noted

Action: MDR

Cnidiadin is an iaolate of Cnidium monnieri (L.) Cuss. (Umbelliferae)

Preliminary studies show some of the compounds in cnidium may have anti-histamine, anti-itch, anti-fungal., and anti-bacterial effects, along with having an influence on the pituitary-adrenocortex axis. Additional studies on rodents indicate that cnidium may improve bone strength (coumarins from fruits of cnidium inhibit formation and differentiation of multinucleated osteoclasts of rats).

In rabbits, a compound found in cnidium called osthol or osthole was found to help relax the corpus cavernosa of the penis, which would potentially help with blood flow and erections. Cnidium may also have anti-cancer properties.

Active Compounds:

Osthole, Imperatorin, Bornyl isovalerate, Cnidimine, Xanthotoxin, Xanthotoxol, Isopimpinelline, Bergapten, Cnidiadin, Cniforin A, Dihydrooroselol, Columbianadin, berapten, cnidiadin, sopimpinellin, imperation, thymine, hypoxanthine (http://www.mdidea.com/products/herbextract/cnidium/data01.html)

MDR

Overexpression of P-glycoprotein (Pgp) encoded by the MDR1 gene is one of the major obstacles to successful cancer chemotherapy. Cnidiadin, a furanocoumarin present in traditional Chinese medications and in a spice commonly used in Greek food, was hence evaluated for its ability to inhibit Pgp transport activity and its potential to reverse MDR1 multi-drug resistance. The dose-dependent increase in [3H]-VBL uptake (IC50 26.5 microM) induced by cnidiadin in the dose range 1–100 microM correlated with inhibition of Pgp photolabeling. At 10 microM cnidiadin inhibited photolabeling by 59% and sensitized both MDCK-MDR1 and KB/VCR cells to vinca alkaloids.

Cnidiadin is a cytotoxic agent capable in vitro of competitively inhibiting the binding and efflux of drug by Pgp and of enhancing the cell toxicity of vinca alkaloids in two cell lines (MDCK-MDR1 and mutant human carcinoma KB/VCR) overexpressing Pgp. This suggests that diet or traditional preparation containing cnidiadin may contribute to the reversal of MDR1 multi-drug resistance and may affect the bioavailability of Pgp substrates orally administered. However, due to its cell toxicity, clinical interest in cnidiadin as a chemo-sensitizer appears to be limited (Barthomeuf et al., 2005).

Reference

Barthomeuf C, Grassi J, Demeule M, et al. (2005). Inhibition of P-glycoprotein transport function and reversion of MDR1 Multi-drug resistance by cnidiadin. Cancer Chemother Pharmacol, 56(2):173-81.