Category Archives: Prostate cancer

anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidative, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, AR, BAX, Bcl-2, Bcl-xL, Breast cancer, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, COX-2, CYP3A, DU145, G1, G2/M, hepato-protective, ICAM-1, inflammation, JNK, MAPK, metastasis, MMP2, MMP9, MTOR, p38, PGE2, Prostate cancer, STAT3, STAT3 (Tyr705), TNF, VCAM-1

Cryptotanshinone (See also Tanshinone)

Cancer:
Prostate, breast, cervical., leukemia, hepatocellular carcinoma

Action: Anti-inflammatory, cell-cycle arrest, inhibits dihydrotestosterone (DHT), anti-proliferative, hepato-protective

Cryptotanshinone is a major constituent of tanshinones from Salvia miltiorrhiza (Bunge).

Tanshinone IIA and cryptotanshinone could induce CYP3A activity (Qiu et al., 2103).

Anti-proliferative Agent

Cryptotanshinone (CPT), a natural compound, is a potential anti-cancer agent. Chen et al., (2010) have shown that CPT inhibited cancer cell proliferation by arresting cells in G(1)-G(0) phase of the cell-cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation.

Furthermore, they found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I- or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel anti-proliferative agent.

Anti-inflammatory; COX-2, PGE2

Cyclooxygenase-2 (COX-2) is a key enzyme that catalyzes the biosynthesis of prostaglandins from arachidonic acid and plays a critical role in some pathologies including inflammation, neurodegenerative diseases and cancer. Cryptotanshinone is a major constituent of tanshinones and has well-documented anti-oxidative and anti-inflammatory effects.

This study confirmed the remarkable anti-inflammatory effect of cryptotanshinone in the carrageenan-induced rat paw edema model. Since the action of cryptotanshinone on COX-2 has not been previously described, in this study, Jin et al. (2006) examined the effect of cryptotanshinone on cyclooxygenase activity in the exogenous arachidonic acid-stimulated insect sf-9 cells, which highly express human COX-2 or human COX-1, and on cyclooxygenases expression in human U937 promonocytes stimulated by lipopolysaccharide (LPS) plus phorbolmyristate acetate (PMA).

Cryptotanshinone reduced prostaglandin E2 synthesis and reactive oxygen species generation catalyzed by COX-2, without influencing COX-1 activity in cloned sf-9 cells. In PMA plus LPS-stimulated U937 cells, cryptotanshinone had negligible effects on the expression of COX-1 and COX-2, at either a mRNA or protein level. These results demonstrate that the anti-inflammatory effect of cryptotanshinone is directed against enzymatic activity of COX-2, not against the transcription or translation of the enzyme.

Prostate Cancer

Cryptotanshinone was identified as a potent STAT3 inhibitor. Cryptotanshinone rapidly inhibited STAT3 Tyr705 phosphorylation in DU145 prostate cancer cells and the growth of the cells through 96 hours of the treatment. Inhibition of STAT3 Tyr705 phosphorylation in DU145 cells decreased the expression of STAT3 downstream target proteins such as cyclin D1, survivin, and Bcl-xL.

Cryptotanshinone can suppress Bcl-2 expression and augment Fas sensitivity in DU145 prostate cancer cells. Park et al. (2010) show that JNK and p38 MAPK act upstream of Bcl-2 expression in Fas-treated DU145 cells, and that cryptotanshinone significantly blocked activation of these kinases. Moreover, cryptotanshinone sensitized several tumor cells to a broad range of anti-cancer agents. Collectively, the data suggest that cryptotanshinone has therapeutic potential in the treatment of human prostate cancer (Park et al., 2010).

Cryptotanshinone was colocalized with STAT3 molecules in the cytoplasm and inhibited the formation of STAT3 dimers. Computational modeling showed that cryptotanshinone could bind to the SH2 domain of STAT3. These results suggest that cryptotanshinone is a potent anti-cancer agent targeting the activation STAT3 protein. It is the first report that cryptotanshinone has anti-tumor activity through the inhibition of STAT3 (Shin et al., 2009).

Prostate Cancer; Androgen Receptor Positive

Anti-androgens to reduce or prevent androgens binding to androgen receptor (AR) are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Xu et al., (2012) found that cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Their results indicated that 0.5 µM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells.

Furthermore, data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation.

Furthermore, they showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.

Breast Cancer, Cervical Cancer, Leukemia, Hepatocellular Carcinoma

The three tanshinone derivatives, tanshinone I, tanshinone IIA, and cryptotanshinone, exhibited significant in vitro cytotoxicity against several human carcinoma cell lines (Wang et al., 2007).

Tanshinone I was found to inhibit the growth and invasion of breast cancer cells both in vitro and in vivo through regulation of adhesion molecules including ICAM-1 and VCAM-1 (Nizamutdinova et al., 2008), and induce apoptosis of leukemia cells by interfering with the mitochondrial transmembrane potential (ΔΨm), increasing the expression of Bax, as well as activating caspase-3 (Liu et al., 2010). Tanshinone IIA has been reported to inhibit the growth of cervical cancer cells through disrupting the assembly of microtubules, and induces G2/M phase arrest and apoptosis (Pan et al., 2010).

This compound can also inhibit invasion and metastasis of hepatocellular carcinoma (HCC) cells both in vitro and in vivo, by suppressing the expression of the metalloproteinases, MMP2 and MMP9 and interfering with the NFκB signaling pathway (Xu et al., 2009).

Breast Cancer

Cryptotanshione was reported to induce cell-cycle arrest at the G1-G0 phase, which was accompanied by the inhibition of cyclin D1 expression, retinoblastoma (Rb) protein phosphorylation, and of the rapamycin (mTOR) signaling pathway (Chen et al., 2010).

Hepato-protective Effect

Cryptotanshinone (20 or 40mg/kg) was orally administered 12 and 1h prior to GalN (700mg/kg)/LPS (10µg/kg) injection. The increased mortality and TNF- α levels by GalN/LPS were declined by cryptotanshinone pre-treatment. In addition, cryptotanshinone attenuated GalN/LPS-induced apoptosis, characterized by the blockade of caspase-3, -8, and -9 activation, as well as the release of cytochrome c from the mitochondria. Furthermore, cryptotanshinone significantly inhibited the activation of NF-κB and suppressed the production of pro-inflammatory cytokines.

These findings suggest that the hepato-protective effect of cryptotanshinone is likely to be associated with its anti-apoptotic activity and the down-regulation of MAPKs and NF-κB associated at least in part with suppressing TAK1 phosphorylation (Jin et al., 2013).

References

Chen W, Luo Y, Liu L, Zhou H, Xu B, Han X, Shen T, Liu Z, Lu Y, Huang S. (2010). Cryptotanshinone Inhibits Cancer Cell Proliferation by Suppressing Mammalian Target of Rapamycin–Mediated Cyclin D1 Expression and Rb Phosphorylation. Cancer Prev Res (Phila), 3(8):1015-25. doi: 10.1158/1940-6207.CAPR-10-0020. Epub 2010 Jul 13.

Jin DZ, Yina LL, Jia XQ, Zhu XZ. (2006). Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression. European Journal of Pharmacology, 549(1-3):166-72. doi:10.1016/j.ejphar.2006.07.055

Jin VQ, Jiang S, Wu YL, et al. (2013). Hepato-protective effect of cryptotanshinone from Salvia miltiorrhiza in d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure. Phytomedicine. doi:10.1016/j.phymed.2013.07.016

Liu JJ, Liu WD, Yang HZ, et al. (2010). Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I-induced apoptosis in myeloid leukemia cells in vitro. Ann Hematol, 89:1089–1097. doi: 10.1007/s00277-010-0996-z.

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

Pan TL, Hung YC, Wang PW, et al. (2010). Functional proteomic and structural insights into molecular targets related to the growth-inhibitory effect of tanshinone IIA on HeLa cells. Proteomics,10:914–929.

Park IJ, Kim MJ, Park OJ, et al. (2010). Cryptotanshinone sensitizes DU145 prostate cancer cells to Fas(APO1/CD95)-mediated apoptosis through Bcl-2 and MAPK regulation. Cancer Lett, 298:88–98. doi: 10.1016/j.canlet.2010.06.006.

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

Shin DS, Kim HN, Shin KD, et al. (2009). Cryptotanshinone Inhibits Constitutive Signal Transducer and Activator of Transcription 3 Function through Blocking the Dimerization in DU145 Prostate Cancer Cells. Cancer Research, 69:193. doi: 10.1158/0008-5472.CAN-08-2575

Wang X, Morris-Natschke SL, Lee KH. (2007). New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev, 27:133–148. doi: 10.1002/med.20077.

Xu D, Lin TH, Li S, Da J, et al. (2012). Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells. Cancer Lett, 316(1):11-22. doi: 10.1016/j.canlet.2011.10.006.

Xu YX, Feng T, Li R, Liu ZC. (2009). Tanshinone II-A inhibits invasion and metastasis of human hepatocellular carcinoma cells in vitro and in vivo. Tumori, 95:789–795.

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-inflammatory, apoptosis, apoptosis induction, AR, blood sugar regulation, Breast cancer, Breast cancer cell lines, Cervical cancer, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, DU145, HT-29, Caco-2, LNCaP and DU145, metastasis, Prostate cancer, S, Vaccinium arctostaphylos

Blueberin

Cancer: Colon, prostate, cervical., breast

Action: Anti-inflammatory, blood sugar regulation

Blueberin is isolated from Vaccinium arctostaphylos (L.).

Colon Cancer

Research has shown that diets rich in phenolic compounds such as those associated with blueberries such as blueberin may be associated with lower risks of several chronic diseases including cancer.

To probe this effect, the bioactivities of various components of blueberries were investigated and their potential anti-proliferation and apoptosis induction effects were investigated using two colon cancer cell lines, HT-29 and Caco-2. Polyphenols in three blueberry cultivars, Briteblue, Tifblue, and Powderblue, were extracted and freeze-dried. The extracts were further separated into phenolic acids, tannins, flavonols, and anthocyanins using an HLB cartridge and LH20 column. The phenolic acid fraction showed relatively lower bioactivities with 50% inhibition at 1000 µg/mL. The greatest anti-proliferation effect among all four fractions was from the anthocyanin fractions. Both HT-29 and Caco-2 cell growth was significantly inhibited by >50% by the anthocyanin fractions at concentrations of 15−50 µg/mL. Anthocyanin fractions also resulted in 2−7 times increase in DNA fragmentation, indicating the induction of apoptosis. The effective dosage levels are close to the reported range of anthocyanin concentrations in rat plasma. These findings suggest that blueberry intake may reduce colon cancer risk (Yi, 2005).

Prostate Cancer; AR+, AR-

The role of polyphenol fractions from both wild and cultivated blueberry fruit was probed in the inhibitory effects on the proliferation of LNCaP, an androgen-sensitive prostate cancer cell line, and DU145, a more aggressive androgen insensitive prostate cancer cell line. When 20µg/ml of a wild blueberry polyphenol fraction was added to LNCaP media, growth was inhibited to 11% of control with an IC50 of 13.3µg/ml. Two similar polyphenol-rich fractions from cultivated blueberries at the same concentration inhibited LNCaP growth to 57% and 26% of control with an IC50 of 22.7 and 5.8µg/ml, respectively. Differences in cell growth inhibition of LNCaP and DU145 cell lines by blueberry fractions rich in polyphenols indicate that blueberry proanthocyanidins have an effect primarily on androgen-dependent growth of prostate cancer cells. Possible molecular mechanisms for growth inhibition are reviewed (Schmidt, 2006).

Prostate Cancer

The mechanism(s) by which three flavonoid-enriched fractions from lowbush blueberry (Vaccinium angustifolium) down-regulate matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells were investigated. Regulation of MMPs is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis. Findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells (Matchett, 2005).

Cervical Cancer, Breast Cancer

Blueberin, extracted with hexane, 50% hexane/ethyl acetate, ethyl acetate, ethanol, and 70% acetone/water at ambient temperature was tested for in vitro anti-cancer activity on cervical and breast cancer cell lines. Ethanol extracts strongly inhibited CaSki and SiHa cervical cancer cell lines and MCF-7 and T47-D breast cancer cell lines. An unfractionated aqueous extract of raspberry and the ethanol extract of blueberry significantly inhibited mutagenesis by both direct-acting and metabolically activated carcinogens (Wedge et al., 2001).

Anti-inflammatory

The reduction of fasting glucose was correlated with the reduction of serum CRP in the Blueberin group whereas in the Placebo group CRP levels were not significantly reduced. Furthermore, the Blueberin also significantly reduced the levels of plasma enzymes ALT, AST and GGT, indicating that, in addition to anti-diabetes effects, the Blueberin also possess pharmacologically relevant anti-inflammatory properties (Abidov et al., 2006).

References

Abidov M, Ramazanov A, Jimenez Del Rio M, Chkhikvishvili I. (2006). Effect of Blueberin on fasting glucose, C-reactive protein and plasma aminotransferases, in female volunteers with diabetes type 2: double-blind, placebo controlled clinical study. Georgian Med News, (141):66-72.

Matchett MD, MacKinnon, L, Sweeney MI, Gottschall-Pass KT, Hurta, RAR. (2006). Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events. The Journal of Nutritional Biochemistry. doi: 10.1016/j.jnutbio.2005.05.014.

Schmidt BM, Erdman Jr JW, Lila MA. (2006). Differential effects of blueberry proanthocyanidins on androgen sensitive and insensitive human prostate cancer cell lines. Cancer Letters, 231(2):240-246. doi: 10.1021/jf049238n.

Wedge DE, Meepagala KM, Magee JB, et al. (2001). Anti-carcinogenic Activity of Strawberry, Blueberry, and Raspberry Extracts to Breast and Cervical Cancer Cells. Journal of Medicinal Food, 4(1):49-51. doi: 10.1089/10966200152053703.

Yi W, Fischer J, Krewer G, Akoh C. (2005). Phenolic Compounds from Blueberries Can Inhibit Colon Cancer Cell Proliferation and Induce Apoptosis. J. Agric. Food Chem, 53(18):7320–7329. doi: 10.1021/jf051333o.

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

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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.


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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.

Anti-cancer, apoptosis, apoptosis induction, Apoptotic, BAX, Bcl-2, Boswellia carterri Birdw, Boswellia serrata, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, DR5, G1, Gastric cancer or Stomach cancer, HT-29, induces apoptosis, LNCaP, PC-3, p21, p53, PARP, Prostate cancer, SGC-7901, MKN-45

Acetyl-keto-beta-boswellic acid (AKBA)

Cancer: Colorectal, prostate, gastric

Action: Anti-cancer

Apoptotic

Acetyl-keto-beta-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation, and independent of Fas/Fas ligand interaction in colon cancer HT-29 cells (Liu et al., 2002).

Colon Cancer

Although there is increasing evidence showing that boswellic acid might be a potential anti-cancer agent, the mechanisms involved in its action are unclear. It has been shown that acetyl-keto-beta-boswellic acid (AKBA) inhibits cellular growth in several colon cancer cell lines. Cell cycle analysis by flow cytometry showed that cells were arrested at the G1 phase after AKBA treatment.

These results demonstrate that AKBA inhibits cellular growth in colon cancer cells. These findings may have implications for the use of boswellic acids as potential anti-cancer agents in colon cancer (Liu et al., 2006).

AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell-cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity (Yuan et al., 2013).

Gastric Cancer

AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited gastric cancer cells line SGC-7901 and MKN-45 xenografts without toxicity.

This effect might be associated with its roles in cell-cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated (Zhang et al., 2013).

Prostate

The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 microg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage.

AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP (Lu et al., 2008).

References

Liu J-J, Nilsson A, Oredsson S, et al. (2002). Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis. 23(12): 2087–2093. doi:10.1093/carcin/23.12.2087.

 

 

Liu JJ, Huang B, Hooi SC. (2006). Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br J Pharmacol, 148(8):1099-107.

 

Lu M, Xia L, Hua H, Jing Y. (2008). Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer Res, 68(4):1180-6. doi: 10.1158/0008-5472.CAN-07-2978.

 

Yuan Y, Cui SX, Wang Y, et al. (2013). Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways. Biochim Biophys Acta, 1830(10):4907-16. doi: 10.1016/j.bbagen.2013.06.039.

 

Zhang YS, Xie JZ, Zhong JL, et al. (2013) Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β -catenin signaling pathway. Biochim Biophys Acta, 1830(6):3604-15. doi: 10.1016/j.bbagen.2013.03.003.

anti-oxidant, anti-tumor, anti-tumor activity, apoptosis, Bcl-2, Chapter 7 Isolates and Cancer Research, chemo-preventive, G2/M, hepato-protective, inflammation, Prostate cancer, S

β Solanine

Cancer: Liver, prostate

Action: Hepato-protective, apoptosis

The black nightshade (Solanum nigrum Linn.) has been widely used in Chinese traditional medicine as a remedy for the treatment of cancer. Solanum nigrum fruit extract could be used as an anti-oxidant and cancer chemo-preventive material. Solanum nigrum is an herbal plant that has been used as hepato-protective and anti-inflammation agent. The anti-tumor activity of solanine, a steroid alkaloid and active constituent isolated from the nightshade has been demonstrated in various cancer cell lines.

Observation of the cell-cycle showed that cells in the G2/M phases disappeared while the number of cells in the S phase increased significantly for treated groups. Western blot showed that solanine decreased the expression of Bcl-2 protein. Therefore, the target of solanine in inducing apoptosis in HepG2 cells seems to be mediated by the inhibition in the expression of Bcl-2 protein (Ji et al., 2008).

Apoptosis

HepG 2 cells were double stained with AO/EB, and morphological changes of the cells treated with solanine were observed using laser confocal scanning microscopy. Cells in treated groups showed typical signs of apoptosis. Staining with TMRE showed that solanine could lower membrane potential, and staining with Fluo-3/AM showed that solanine could increase the concentration of calcium in tumor cells; those double stained with TMRE and Fluo-3/AM showed that solanine could increase the concentration of calcium in the cells at the same time as it lowered the membrane potential of mitochondria.

Sola was found to open up the PT channels in the membrane by lowering the membrane potential, leading to calcium being transported down its concentration gradient, which in turn led to the rise of the concentration of calcium in the cell, turning on the mechanism for apoptosis (Gao et al., 2006).

Hepato-protective

Solanine (SNE) also has hepato-protective activity against CCl4-induced hepatic damage in rats. The results of the study suggest that Solanum nigrum protects liver against the CCl4-induced oxidative damage in rats, and this hepato-protective effect might be contributed to its modulation on detoxification enzymes and its anti-oxidant and free radical scavenger effects. Oral administration of SNE significantly reduces Thioacetamide -induced hepatic fibrosis in mice, probably through the reduction of transforming growth factor-β1 secretion. It also protects against hepatitis B virus infection B10 (Kaushik et al., 2009).

Prostate Cancer

Solanine has an anti-prostate cancer effect by inhibiting PC-3 cell proliferation, arresting the S phase, inducing cell apoptosis, up-regulating the protein expression of I(kappa)B(alpha) and down-regulating that of Bcl-2. Solanine suppressed the growth of PC-3 cells in a dose- and time-dependent manner in vitro, with significant differences among different concentration and time groups (P < 0.05).

The cycle of the PC-3 cells was arrested in the S phase (P < 0.05), with a significantly higher rate of apoptosis in the treated groups than in the controls (P < 0.05). The protein expression of I(kappa)B(alpha) was obviously up-regulated and that of Bcl-2 down-regulated in all the solanine concentration groups (Zhang & Shi, 2011).

References

Gao SY, Wang QJ, Ji YB. (2006). Effect of solanine on the membrane potential of mitochondria in HepG2 cells and [Ca2+] i in the cells. World J Gastroenterol, 12(21):3359-3367


Ji YB,Gao SY, Ji CF, Zou X. (2008). Induction of apoptosis in HepG2 cells by solanine and Bcl-2 protein. Journal of Ethnopharmacology, 115(2):194-202. doi:10.1016/j.jep.2007.09.023


Kaushik D, Jogpal V, Kaushik P, Lal S et al. (2009). Evaluation of activities of Solanum nigrum fruit extract. Archives of Applied Science Research, 1(1):43-50


Zhang J, Shi GW. (2011). Inhibitory effect of solanine on prostate cancer cell line PC-3 in vitro. Zhonghua Nan Ke Xue, 17(3):284-7.

Angelica gigas, Angelica gigas (Nakai), angiogenesis, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Fibrosarcoma, IL-8, inflammation, JAK2, MDR, MTOR, p53, PARP, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

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

Oridonin

Cancer: Prostate

Action: Growth arrest, autophagy

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

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

 

Cancer: Multiple myeloma

Action: Inhibits proliferation and induces apoptosis

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

Source:

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

Cancer: Multiple myeloma

Action: Induces apoptosis and autophagy

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

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

Source

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

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

Action: Chemoresistance, Ara-C, VP-16 

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

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

Reference

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

Action: Induces apoptosis

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

Gastric Cancer, Esophageal Cancer, Liver Cancer, Prostate Cancer

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

Induces Apoptosis

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

Anti-cancer

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

Prostate Cancer, Breast Cancer, NSCLC, Leukemia, Glioblastoma

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

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

Breast Cancer; Anti-metastatic

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

Gastric Cancer

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

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

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

Ehrlich Ascites, Leukemia

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

Prostate Cancer, Breast Cancer, Ovarian Cancer

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

Ovarian Cancer Stem Cells; Chemotherapy Resistance

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

Colorectal Cancer

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

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

Colon Cancer; Apoptosis

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

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

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

Prostate Cancer; Apoptosis

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

References

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

180, Angelica gigas, Angelica gigas (Nakai), angiogenesis, Anti-cancer, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, Chemotherapy, Fibrosarcoma, HT1080, IL-8, inflammation, JAK2, MDR, MTOR, p53, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

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

Carnosol

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

Action: Anti-inflammatrory, anti-angiogenic

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

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

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

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

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

Anti-inflammatory

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

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

Breast Cancer

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

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

Anti-angiogenic

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

References:

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


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


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


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


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

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.

Angelica sinensis, Anti-metastastatic, apoptosis, Atg5, Autophagy, Breast cancer, Chapter 7 Isolates and Cancer Research, metastasis, MTOR, PC3 and DU145, phospho-MTOR, Prostate cancer

Sulforaphane

Cancer: Breast cancer, prostate cancer

Action: Anti-metastastatic

Prostate Cancer

Sulforaphane is isolated from varieties of broccoli and other edible cruciferous vegetables as well as the root of Angelica sinensis (Oliv.) Diels (abbreviated as AS) (Danggui), which has a long history in Asian herbal medicine. A major constituent of Angelica sinensis, sulforaphane, is also found in cruciferous vegetables. It inhibits myostatin and increases cell viability in skeletal muscle satellite cells (Alway et al., 2002).

There is preclinical evidence that oral administration of D,L-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer (PIN) and well-differentiated cancer (WDC), but not late-stage poorly differentiated cancer (PDC). SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN+CQ was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN+CQ exposure/response (Vyas et al., 2013a).

Exposure of PC-3 and DU145 human prostate cancer cells to D,L-Sulforaphane (SFN) resulted in induction of vimentin protein, which was accompanied by down-regulation of E-cadherin protein expression. The SFN-mediated induction of vimentin was also observed in a normal human prostate epithelial cell line. RNA interference of vimentin did not have any appreciable effect on early or late apoptosis resulting from SFN exposure.

On the other hand, SFN-mediated inhibition of PC-3 and DU145 cell migration was significantly augmented by knockdown of the vimentin protein. Knockdown of vimentin itself was inhibitory against cell migration. The SFN-treated cells also exhibited induction of PAI-1, which is an endogenous inhibitor of urokinase-type plasminogen activator system (Vyas & Singh, 2013b).

References

Alway SE, Degens H, Lowe DA, Krishnamurthy G. (2002). Increased myogenic repressor Id mRNA and protein levels in hindlimb muscles of aged rats. Am J Physiol Regul Integr Comp Physiol, 282(2):R411-22.


Totušek J, Tříska J, Lefnerová D, et al. (2011). Contents of Sulforaphane and Total Isothiocyanates, Antimutagenic Activity, and Inhibition of Clastogenicity in Pulp Juices from Cruciferous Plants. Czech J. Food Sci, 29(5): 548–556.


Vermeulen M, Klšpping-Ketelaars IW, van den Berg R, Vaes WH. (2008). Bioavailability and kinetics of sulforaphane in humans after consumption of cooked versus raw broccoli. J Agric Food Chem, 56(22):10505-9.


Vyas AR, Hahm E-R, Arlotti JA, et al. (2013a). Chemoprevention of Prostate Cancer by D,L-Sulforaphane Is Augmented by Pharmacological Inhibition of Autophagy. Cancer Research, 73(17). doi: 10.1158/0008-5472.CAN-13-0755


Vyas AR, Singh SV. (2013b). Functional relevance of D,L-sulforaphane-mediated induction of vimentin and plasminogen activator inhibitor-1 in human prostate cancer cells. Eur J Nutr..

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, Akt/mTOR/P70S6K, angiogenesis, Anti-angiogenic, apoptosis, apoptosis-inducing, Apoptotic, BAX, Chapter 7 Isolates and Cancer Research, fruits, grains, HepG2, leaves, Mcl-1, MDA-MB-468, MDR, metastasis, MTOR, P70S6K, Prostate cancer, red wine, vegetables, VEGF, VEGF

Quercetin

Cancer: Leukemia, prostate

Action: MDR, apoptosis-inducing

Quercetin is a plant-derived flavonol found in many fruits, vegetables, leaves and grains. It is also found in red wine.

MDR/ Apoptotic-inducing

Natural products from plants such as flavonoids are potential drugs to overcome multi-drug resistance (MDR) in cancer treatments. Quercetin exhibits cytotoxicity against erythroleukemic cells: IC50 are 11.0 +/- 2.0 micromol/L and 5.0 +/- 0.4 micromol/L for K562 and K562/adr, respectively. Quercetin induces cell death via apoptosis in both K562 and K562/adr cells and does not inhibit Pgp-mediated efflux of 99mTc-MIBI. Quercetin (10 micromol/L, 3 h) and etoposide (100 micromol/L, 24 hours) induce similar levels of apoptosis in K562 and K562/adr cells.

Quercetin induces an increase followed by a decrease in inner mitochondrial membrane potential   |DeltaPsim| value depending on its concentration. A decrease in the |DeltaPsim| value is associated with an increase in the percentage of early apoptotic cells.

It is clearly shown that quercetin results in a spontaneous DeltaPsim change during apoptotic induction. Therefore, quercetin is potentially an apoptotic-inducing agent, which reacts at the mitochondrial level (Kothan et al., 2004).

MDR

Expression of the MDR1 gene, which encodes P-glycoprotein, is increased under some stress conditions. It has been reported that quercetin, a bioflavonoid, inhibits the expression of heat-shock proteins. The effects of quercetin have been identified on the MDR1 gene expression in the human hepatocarcinoma cells line, HepG2. The increase of P-glycoprotein synthesis and MDR1 mRNA accumulation caused by exposure to arsenite were inhibited by quercetin. Although many drugs that prevent the P-glycoprotein function have been reported, this is the first report to describe the inhibition of MDR1 expression by a reagent (Kioka et al., 1992).

Leukemia

Leukemia cells were treated with quercetin, after which apoptosis, Mcl-1 expression, and Bax activation and translocation were evaluated. Quercetin-induced apoptosis was accompanied by Mcl-1 down-regulation and Bax conformational change and mitochondrial translocation that triggered cytochrome c release. In vivo administration of quercetin attenuated tumor growth in U937 xenografts. The TUNEL-positive apoptotic cells in tumor sections increased in quercetin-treated mice as compared with controls.

These data suggest that quercetin may be useful for the treatment of leukemia by preferentially inducing apoptosis in leukemia versus normal hematopoietic cells through a process involving Mcl-1 down-regulation, which, in turn, potentiates Bax activation and mitochondrial translocation, culminating in apoptosis (Cheng et al., 2010).

Prostate Cancer

The anti-angiogenic activity of quercetin was probed using ex vivo, in vivo and in vitro models. Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis.

Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the down-regulation of AKT, mTOR and P70S6K expressions. Collectively, these results suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy (Pratheeshkumar et al., 2012).

References

Cheng SP, Gao N, Zhang Z, et al. (2010). Quercetin Induces Tumor-Selective Apoptosis through Down-regulation of Mcl-1 and Activation of Bax. Clin Cancer Res, 16(23):5679-91. doi: 10.1158/1078-0432.CCR-10-1565


Kioka N, Hosokawa N, Komano T, Hirayoshi K, Nagate K, Ueda K. (1992). Quercetin, a bioflavonoid, inhibits the increase of human Multi-drug resistance gene (< i> MDR1</i>) expression caused by arsenite. FEBS Lett, 301(3):307-9.


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 Pharmacol, 82(12):1084-90.


Pratheeshkumar P, Budhraja A, et al. (2012). Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways. PLoS One, 7(10):e47516. doi: 10.1371/journal.pone.0047516.

ABC, Anti-cancer, anti-inflammatory, anti-metastasis, Anti-metastatic, anti-oxidant, anti-proliferative, apoptosis, apoptosis induction, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Bladder cancer, Breast cancer, c-Fos, c-Jun, CDC2, CDC25A, CDC25C, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, ER, ERK1, G1, G2/M, hTERT, JNK, Lung cancer, lymphangiogenesis inhibitor, lymphangiogenesis inhibitors, MCF-7, MCF-7, MDA-MB-231, MDA-MB-231, MDR, metastasis, MPSC1 (PT), A2780 (PT) and SKOV3 (PT), Nausea and Vomiting, NFATc1, Ovarian cancer, p21, p38, p53, PARP, Pro-apoptotic, pro-oxidative, Prostate cancer, ROS, S, Sarcoma, T24, TIMP-2, TNF

Costunolide and Dehydrocostus Lactone

Cancers:
Breast, cervical., lung, ovarian, bladder, leukemia, prostate, gastric

Action: Anti-inflammatory, pro-oxidative, MDR, lymphangiogenesis inhibitor, anti-metastasis, mediates apoptosis, anti-metastatic

Components of Saussurea lappa Clarke, Vladimiria souliei (Franchet) Lingelsheim (Compositae)

Breast cancer; Anti-metastatic

It was found that costunolide inhibited the growth and telomerase activity of MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner. The expression of hTERT mRNA was also inhibited but hTR mRNA was not. In addition, the bindings of transcription factors in hTERT promoters were significantly decreased in both cells by the treatment of costunolide. These results suggest that costunolide inhibited the growth of both MCF-7 and MDA-MB-231 cells and this effect was mediated at least in part by a significant reduction in telomerase activity (Choi et al., 2005).

Breast Cancer

Costunolide has been demonstrated to suppress tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNF-α induced NF-kB activation. Costunolide also inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays.

In addition, costunolide inhibited in vitro TNF-α induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNF-α induced NF-kB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-kB-dependent gene to mediate breast cancer cell growth and metastases. Taken together, these results suggest that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNF-α induced NF-k B activation, suggesting that costunolide as well as SLC may be promising anti-cancer drugs, especially for metastatic breast cancer (Choi et al., 2013).

Several Chinese herbs, namely, Herba Taraxaci Mongolici (Pu Gong Ying), Radix Glycyrrhizae Uralensis (Gan Cao), Radix Bupleuri (Chai Hu), Radix Aucklandiae Lappae/ Radix Aucklandiae Lappae (Mu Xiang), Fructus Trichosanthis (Gua Lou) and Rhizoma Dioscoreae Bulbiferae (Huang Yao Zi) are frequently used in complex traditional Chinese medicine formulas for breast hyperplasia and breast tumor therapy.

The pharmacological effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. A bioactivity-oriented screening platform, which was based on a human breast cancer MCF-7 cellular model was developed to rapidly screen the 6 Chinese herbs. Two potential anti-breast cancer compounds, which were costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in Radix Aucklandiae Lappae.

Combination of the two compounds showed a synergism on inhibiting the proliferation of MCF-7 cells in vitro, which exhibits a potential application prospect for breast cancer therapy. This bioactivity-oriented screening strategy is rapid, economical., reliable and specific for screening potential anti-breast cancer compounds in traditional Chinese medicines (Peng et al., 2013).

Dehydrocostuslactone (DHE) suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G(0)/G(1)-S phase arrest in MCF-7 cells. In contrast, DHE caused S-G(2)/M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell-cycle progression and cell death through SOCS-1 and SOCS-3.

Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer (Kuo et al., 2009).

ER- Breast Cancer

Costunolide induced apoptosis through the extrinsic pathway, including the activation of Fas, caspase-8, caspase-3, and degradation of PARP. However, it did not have the same effect on the intrinsic pathway as revealed by analysis of mitochondrial membrane potential (Δψ m) with JC-1 dye and expression of Bcl2 and Bax proteins level.

Furthermore, costunolide induced cell-cycle arrest in the G2/M phase via decrease in Cdc2, cyclin B1 and increase in p21WAF1 expression, independent of p53 pathway in p53-mutant MDA-MB-231 cells, and increases Cdc2-p21WAF1 binding/

Through this study it was confirmed that costunolide induces G2/M cell-cycle arrest and apoptotic cell death via extrinsic pathway in MDA-MB-231 cells, suggesting that it could be a promising anti-cancer drug especially for ER negative breast cancer (Choi et al., 2012).

Bladder Cancer

Costunolide, a member of sesquiterpene lactone family, possesses potent anti-cancer properties. The effects of costunolide were investigated on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis, which was associated with the generation of ROS and disruption of mitochondrial membrane potential (Δψm).

These effects were significantly blocked when the cells were pre-treated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, and of   survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer (Rasul et al., 2013).

Sarcomas; MDR

Human soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment.

The effects on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. Cells treated with costunolide showed no changes in cell-cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 hours. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction.

These data demonstrate that dehydrocostus lactone affects cell viability, cell-cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumors (Kretschmer et al., 2013).

Leukemia, Lung Cancer

Costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, has been found to induce apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. Mitogen-activated protein kinases (MAPKs) were investigated for their involvement in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells.

Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 minutes of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis.

Furthermore, pre-treatment with the anti-oxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 days) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model (Choi et al., 2009).

Prostate Cancer

Several pharmacological and biochemical assays were used to characterize the apoptotic-signaling pathways of costunolide in prostate cancer cells. Costunolide showed effective anti-proliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC¨) by sulforhodamine B assay, clonogenic test and flow cytometric analysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells data showed that costunolide induced a rapid overload of nuclear Ca(2+), DNA damage response and ATR phosphorylation.

This indicated the crucial role of intracellular Ca(2+) mobilization and thiol depletion but not of reactive oxygen species production in apoptotic signaling. Data suggest that costunolide induces the depletion of intracellular thiols and overload of nuclear Ca(2+) that cause DNA damage and p21 up-regulation. The association of p21 with the cyclin dependent kinase 2/cyclin E complex blocks cyclin dependent kinase 2 activity and inhibits Rb phosphorylation, leading to G1 arrest of the cell-cycle and subsequent apoptotic cell death in human prostate cancer cells (Hsu et al., 2011).

Gastric Cancer, Prostate Cancer

Radix Aucklandiae Lappae/Saussurea lappa has been used in Chinese traditional medicine for the treatment of abdominal pain, tenesmus, nausea, and cancer; previous studies have shown that S. lappa also induces G(2) growth arrest and apoptosis in gastric cancer cells. The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated.

The active compound, dehydrocostus lactone (DHCL), in fraction 7 dose-dependently inhibited the basal and EGF-induced migration of prostate cancer cells. HESL and DHCL reduced matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 secretion but increased TIMP-2 levels in both the absence and presence of EGF. These results demonstrate that the inhibition of MMP-9 secretion and the stimulation of TIMP-2 secretion contribute to reduced migration of DU145 cells treated with HESL and DHCL.

This indicates that HESL containing its active principle, DHCL, has potential as an anti-metastatic agent for the treatment of prostate cancer (Kim et al., 2012).

Anti-metastatic

Lymphangiogenesis inhibitors from crude drugs used in Japan and Korea were investigated for their impact on metastasis. The three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro.

Among isolated compounds, several compounds; costunolide, dehydrocostus lactone, psoracorylifol D, bavachinin, bakuchiol, showed an inhibitory effect on the proliferation and the capillary-like tube formation of TR-LE cells. In addition, all compounds showed selective inhibition of the proliferation of TR-LE cells compared to Hela and Lewis lung carcinoma (LLC) cells.

These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong et al., 2013).

Ovarian Cancer, MDR

The apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, was studied in platinum-resistant human ovarian cancer cells relative to cisplatin.

The MTT assay for cell viability, PI staining for cell-cycle profiling, and annexin V assay for apoptosis analysis were performed. Costunolide induced apoptosis of platinum-resistant cells in a time and dose-dependent manner and suppressed tumor growth in the SKOV3 (PT)-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, caspase-8, and caspase-9. Pre-treatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.

Data suggests that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancers (Yang, Kim, Lee, & Choi, 2011).

Anti-inflammatory, Anti-oxidant, Mediates Apoptosis

Cheon et al. (2013) found that costunolide significantly inhibited RANKL-induced BMM differentiation into osteoclasts in a dose-dependent manner without causing cytotoxicity. Costunolide did not regulate the early signaling pathways of RANKL, including the mitogen-activated protein kinase and NF-κB pathways.

However, costunolide suppressed nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression via inhibition of c-Fos transcriptional activity without affecting RANKL-induced c-Fos expression. The inhibitory effects of costunolide were rescued by overexpression of constitutively active (CA)-NFATc1. Taken together, these results suggest that costunolide inhibited RANKL-induced osteoclast differentiation by suppressing RANKL-mediated c-Fos transcriptional activity.

References

Cheon YH, Song MJ, Kim JY, Kwak SC, Park JH, Lee CH, Kim JJ, Kim JY, Choi MK, Oh J, Kim YC, Yoon KH., Kwak HB, Lee MS. (2013). Costunolide inhibits osteoclast differentiation by suppressing c-Fos transcriptional activity. Phytotherapy, July, (6). doi: 10.1002/ptr.5034.

Choi SH, Im E, Kang HK, et al. (2005). Inhibitory effects of costunolide on the telomerase activity in human breast carcinoma cells. Cancer Lett, 227(2):153-62.


Choi JH, Lee KT. (2009). Costunolide-induced apoptosis in human leukemia cells: involvement of c-jun N-terminal kinase activation. Biol Pharm Bull, 32(10):1803-8.


Choi YK, Seo HS, Choi HS, et al. (2012). Induction of Fas-mediated extrinsic apoptosis, p21WAF1-related G2/M cell-cycle arrest and ROS generation by costunolide in estrogen receptor-negative breast cancer cells, MDA-MB-231. Mol Cell Biochem, 363(1-2):119-28. doi: 10.1007/s11010-011-1164-z.


Choi YK, Cho S-G, Woo S-M, et al. (2013). Saussurea lappa Clarke-Derived Costunolide Prevents TNF α-Induced Breast Cancer Cell Migration and Invasion by Inhibiting NF-κ B Activity. Evidence-Based Complementary and Alternative Medicine. doi:10.1155/2013/936257.


Hsu JL, Pan SL, Ho YF, Het al. (2011). Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. The Journal of Urology, 185(5):1967-74. doi: 10.1016/j.juro.2010.12.091.


Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biol Pharm Bull, 36(1):152-7.


Kim EJ, Hong JE, Lim SS, et al. (2012). The hexane extract of Saussurea lappa and its active principle, dehydrocostus lactone, inhibit prostate cancer cell migration. J Med Food, 15(1):24-32. doi: 10.1089/jmf.2011.1735.


Kretschmer N, Rinner B, Stuendl N, et al. (2012). Effect of costunolide and dehydrocostus lactone on cell-cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Planta Med, 78(16):1749-56. doi: 10.1055/s-0032-1315385.


Kuo PL, Ni WC, Tsai EM, Hsu YL. (2009). Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells. Mol Cancer Ther, 8(5):1328-39. doi: 10.1158/1535-7163.MCT-08-0914.


Peng ZX, Wang Y, Gu X, Wen YY, Yan C. (2013). A platform for fast screening potential anti-breast cancer compounds in traditional Chinese medicines. Biomed Chromatogr. doi: 10.1002/bmc.2990.


Rasul A, Bao R, Malhi M, et al. (2013). Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. Molecules, 18(2):1418-33. doi: 10.3390/molecules18021418.


Yang YI, Kim JH, Lee KT, & Choi JH. (2011). Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species. Gynecologic Oncology, 123(3), 588-96. doi: 10.1016/j.ygyno.2011.08.031.

anti-tumor, apoptosis, Apoptotic, AT6.3, Breast cancer, Chapter 7 Isolates and Cancer Research, Enhances tamoxifen, PARP, Prostate cancer, Radio-sensitizer, radio-sensitizing

Daidzein & S-(-)-equol

Cancer: Breast, prostate

Action: Enhances tamoxifen, radio-sensitizer

Daidzein & Genistein Concentrations; Breast Cancer

A systematic search by Mário L de Lemos (2001) through primary English-language literature on MEDLINE (1966–January 2001), EMBASE (1982–January 2001) and Current Contents (1998–January 2001) found that genistein and daidzein at low concentrations were found to stimulate breast tumor growth in in vitro and in vivo animal studies, and antagonize the anti-tumor effect of tamoxifen in vitro. However, at high concentrations, genistein inhibited tumor growth and enhanced the effect of tamoxifen in vitro.

At concentrations below 10 µmol/L, phytoestrogens can stimulate breast tumor growth and antagonize the anti-tumor effects of tamoxifen, particularly in an environment of low endogenous estrogen. In contrast, phytoestrogens inhibit breast tumor growth and enhance the anti-tumor effects of tamoxifen at concentrations above 10 µmol/L (de Lemos, 2002; Akaza et al., 2004).

Breast cancer

Daidzein or its major metabolite equol at a dose molar equivalent to tamoxifen [1.0 mg(2.7 µmol)/kg or 10 mg (27 µmol)/kg/day] was treated orally to rats bearing 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors or ovariectomized athymic nude mice implanted with human MCF-7 breast cancer xenograft and an estrogen pellet. The growth of tumors was monitored for several weeks after the treatment. The cell-cycle and apoptotic stages in mammary tumors collected from rats were analyzed by flow cytometry. Immunohistochemistry analysis was also used to determine the expression of caspase-3.

Oral treatment with daidzein or equol at a human equivalent dose suppressed the growth of both DMBA-induced mammary tumors and human MCF-7 breast cancer xenografts in rodents, the inhibitory activity being superior to that of genistein or tamoxifen. Strong apoptosis induced by daidzein or equol contributes to the anti-tumor potential.

Daidzein and its metabolite equol showed the potential of inhibiting the growth of mammary tumors in rodents. Daidzein or equol could be used as a core structure to design new drugs for breast cancer therapy. Our results indicate that consumption of daidzein may protect against breast cancer (Liu et al., 2012).

Equol Production

S-(-)-equol is a metabolite of the soy isoflavone daidzein and is produced by intestinal bacteria in some, but not in all, humans after soy consumption (Setchell & Clerici, 2010). The ability of S-equol to play a role in the treatment of estrogen or androgen-mediated diseases or disorders was first proposed in 1984 (Setchell et al., 1984). The ability to do so depends on two things: soy and bacteria. First, the soy must contain the soy isoflavone daidzein and the amount may influence equol production. Second, the human must have certain strains of bacteria living within the intestine. Twenty-one different strains of intestinal bacteria cultured from humans have the ability to transform daidzein into S-equol or a related intermediate compound (Setchell & Clerici, 2010).

Several studies indicate that only 25 to 30 percent of the adult population of Western countries produces S-equol after eating soy foods containing isoflavones, (Rowland et al., 2000; Atkinson et al., 2005) significantly lower than the reported 50–60% frequency of equol-producers in adults from Japan, Korea, or China (Song et al., 2006).

Equol Production; Prostate Cancer

Akaza et al. (2004) recently conducted a case-controlled study on those who are able to degrade daidzein, a soybean isoflavone, to equol and those without this ability. The incidence of prostate cancer is known to be lower in residents in Japan. On the other hand, American residents in the United States have a markedly higher incidence of prostate cancer.

The number of subjects was 295 in Japan (133 patients and 162 controls), 122 in Korea (61 patients and 61 controls) and 45 in the United States (24 patients and 21 controls). The percentage of equol producers among patients and controls was 29% and 46% in Japan (P = 0.004) and 30% and 59% in Korea (P = 0.001), respectively. The active isoflavone level was markedly lower and the percentage of equol producers was also lower (17% for patients and 14% for controls) for Americans as compared to the Japanese and Koreans.

These results suggest that the ability to produce equol, or equol itself, is closely related to the lower incidence of prostate cancer. The results also suggest that a diet based on soybean isoflavones will be useful in preventing prostate cancer.

Prostate cancer

The age-adjusted incidence rate of prostate cancer (PCa) has been reported to be lower among Asians than Western populations. A traditional Japanese meal., high in soybean products or isoflavones, may be associated with a decreased risk of PCa. Equol, which is converted from daidzein by human intestinal flora, is biologically more active than any other isoflavone aglycone.

Five out of 6 articles showed significant association of isoflavones with a decreased risk of PCa, and two of them consistently showed that equol-producers carry a significantly reduced risk of PCa. Furthermore, 5 human intestinal bacteria that can convert daidzein into equol were identified in the last 5 years. If equol can reduce risk of PCa, a possible strategy for reducing the risk of PCa may be to increase the proportion of equol-producers by changing the intestinal flora to carry an equol-producing bacterium, with dietary alteration or probiotic technology (Sugiyama et al., 2013).

Equol Enhances Tamoxifen

Charalambous, Pitta, & Constantinou (2013) found that equol (>50  µM) and 4-hydroxy-tamoxifen (4-OHT; >100 nM) significantly reduced the breast cancer MCF-7 cell viability. Furthermore, the combination of equol (100 µM) and 4-OHT (10 µM) induced apoptosis more effectively than each compound alone. Subsequent treatment of MCF-7 cells with the pan-caspase inhibitor Z-VAD-FMK inhibited equol- and 4-OHT-mediated apoptosis, which was accompanied by PARP and α-fodrin cleavage, indicating that apoptosis is mainly caspase-mediated.

Equol may be used therapeutically in combination treatments and clinical studies to enhance tamoxifen's effect by providing additional protection against estrogen-responsive breast cancers.

Radio-sensitizer

Sensitivity of cells to equol, radiation and a combination of both was determined by colonogenic assays. Induction of apoptosis by equol, radiation and the combination of both was also determined by acridine orange/ethidium bromide double staining fluorescence microscopy. DNA strand breaks were assessed by Comet assay.

MTT assay showed that equol (0.1-350 µM) inhibited MDA-MB-231 and T47D cell growth in a time- and dose-dependent manner. Treatment of cells with equol for 72 hours (MDA-MB-231) and 24 hours (T47D) was found to inhibit cell growth with IC50 values of 252 µM and 228 µM, respectively. Furthermore, pre-treatment of cells with 50 µM equol for 72 hours (MDA-MB-231) and 24 hours (T47D) sensitized the cells to irradiation. Equol was also found to enhance radiation-induced apoptosis. Comet assay results showed that the radio-sensitizing effect of equol was accompanied by increased radiation-induced DNA damage.

These results suggest for the first time that equol can be considered as a radio-sensitizing agent and its effects may be due to increasing cell death following irradiation, increasing the remaining radiation-induced DNA damage and thus reducing the surviving fraction of irradiated cells (Taghizadeh et al., 2013).

References

Akaza H, Miyanaga N, Takashima N, Naito S, et al. (2004). Comparisons of percent equol producers between prostate cancer patients and controls: case-controlled studies of isoflavones in Japanese, Korean and American residents. Japanese Journal of Clinical Oncology, 34(2): 86–9.


Atkinson, C., Frankenfeld, C.L., Lampe, J.W. (2005). Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Experimental Biology and Medicine (Maywood, N.J.), 230(3):155–70.


Charalambous C, Pitta CA, Constantinou AI. (2013). Equol enhances tamoxifen's anti-tumor activity by induction of caspase-mediated apoptosis in MCF-7 breast cancer cells. BMC Cancer, 13:238. doi: 10.1186/1471-2407-13-238.


de Lemos ML. (2001). Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacother, 35(9):1118-21.


de Lemos ML. (2002). Safety Issues of Soy Phytoestrogens in Breast Cancer Patients. JCO, 20(13):3040-3042.


Liu X, Suzuki N, Santosh Laxmi YR, Okamoto Y, Shibutani S. (2012). Anti-breast cancer potential of daidzein in rodents. Life Sci, 91(11-12):415-9.


Rowland IR, Wiseman H, Sanders TA, Adlercreutz H, Bowey EA. (2000). Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutrition and Cancer, 36(1):27–32. doi:10.1207/S15327914NC3601_5.


Setchell KD, Borriello SP, Hulme P, Kirk DN, Axelson M. (1984). Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. The American Journal of Clinical Nutrition, 40(3):569–78.


Setchell KD, Clerici C. (2010). Equol: history, chemistry, and formation. The Journal of Nutrition, 140 (7): 1355S–62S. doi:10.3945/jn.109.119776.


Song KB, Atkinson C, Frankenfeld CL, Jokela T, et al. (2006). Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls. The Journal of Nutrition, 136(5):1347–51.


Sugiyama Y, Masumori N, Fukuta F, et al. (2013). Influence of isoflavone intake and equol-producing intestinal flora on prostate cancer risk. Asian Pac J Cancer Prev, 14(1):1-4.


Taghizadeh B, Ghavami L, Nikoofar A, Goliaei B. (2013). Equol as a potent radiosensitizer in estrogen receptor-positive and -negative human breast cancer cell lines. Breast Cancer.

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

Tanshinone II A & Tanshinone A (See also Cryptotanshinone)

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

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

Anti-cancer

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

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

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

Leukemia

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

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

Prostate Cancer

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

Gastric Cancer

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

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

Cell-cycle Arrest

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

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

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

Prostate Cancer, Chemo-sensitizer

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

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

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

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

Autophagic Cell Death, CSCs

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

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

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

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

Colorectal Cancer

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

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

Breast Cancer

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

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

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

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

Nasopharyngeal Carcinoma

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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

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

Apigenin

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

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

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

Induces Apoptosis, Anti-metastatic

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

Chemo-sensitizer, Induces Apoptosis

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

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

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

Breast Cancer, Prostate Cancer

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

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

Ovarian Cancer

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

Pancreatic Cancer

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

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

Induces Apoptosis, Inhibits Angiogenesis and Metastasis.

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

Lung Cancer

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

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

Induces Apoptosis

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

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

Colorectal Cancer

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

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

References

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

 

 

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

 

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

 

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

 

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

 


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

 

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

 

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

 

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