Category Archives: induces apoptosis

Akt, Anti-cancer, anti-inflammatory, anti-proliferative, AP-1, apoptosis, Apoptotic, B16F10, BGC-803, Breast cancer, c-Jun, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, Chemo-preventive agent, chemo-sensitizing, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, COX-2 inhibitor, Cytostatic, cytostatic effect, cytotoxic, Esophageal cancer, FasL, G0/G1, G1, G2/M, Gastric cancer or Stomach cancer, H22, HL-60, HT-29, Hyptis capitata, IL-1, induces apoptosis, inhibits proliferation, JNK, Lung cancer, MCF-7, MDA-MB-231, MMP2, NAD(P)H, p65, PC3, Prostate cancer, Prunella vulgaris, Psychotria serpens, Rectal cancer, ROS, Rosmarinus officinalis, S, Salvia officinalis, T24, u-PA, YES-2

Ursolic acid

Cancer:
Glioblastoma, Lung, breast, colorectal, gastric, esophageal squamous carcinoma, prostate

Action:

Mitochondrial function, reactive oxygen species (ROS) generation.

Cytostatic, anti-inflammatory, chemo-prevention, COX-2 inhibitor, suppresses NF- κ B, induces IL-1 β , induces apoptosis

Ursolic acid, a pentacyclic triterpene acid found ubiquitously in the plant kingdom, including Rosmarinus officinalis (L.), Salvia officinalis (L.), Prunella vulgaris (L.), Psychotria serpens (L.) and Hyptis capitata (Jacq.). It has been shown to suppress the expression of several genes associated with tumorigenesis resulting in anti-inflammatory, anti-tumorigenic and chemo-sensitizing effects (Liu, 1995).

Glioblastoma Cancer

Ursolic acid, a natural pentacyclic triterpenic acid, possesses anticancer potential and diverse biological effects, but its correlation with glioblastoma multiforme cells and different modes of cell death is unclear. We studied the cellular actions of human GBM DBTRG-05MG cells after ursolic acid treatment and explored cell-selective killing effect of necrotic death as a cell fate.

Ursolic acid effectively reversed TMZ resistance and reduced DBTRG-05MG cell viability. Surprisingly, ursolic acid failed to stimulate the apoptotic and autophagic-related signaling networks. The necrotic death was characterized by annexin V/PI double-positive detection and release of HMGB1 and LDH. These ursolic acid-elicited responses were accompanied by ROS generation and glutathione depletion. Rapid mitochondrial dysfunction was paralleled by the preferential induction of necrosis, rather than apoptotic death. MPT is a phenomenon to provide the onset of mitochondrial depolarization during cellular necrosis. The opening of MPT pores that were mechanistically regulated by CypD, and ATP decline occurred in treated necrotic DBTRG-05MG cells. Cyclosporine A (an MPT pore inhibitor) prevented ursolic acid-provoked necrotic death and -involved key regulators.

The study by Lu et al., (2014) is the first to report that ursolic acid-modified mitochondrial function triggers defective death by necrosis in DBTRG-05MG cells rather than augmenting programmed death.

Gastric Cancer

Ursolic acid (UA) inhibits growth of BGC-803 cells in vitro in dose-dependent and time-dependent manner. Treated with UA in vivo, tumor cells can be arrested to G0/G1 stage. The apoptotic rate was significantly increased in tumor cells treated with UA both in vitro and in vivo. These results indicated that UA inhibits growth of tumor cells both in vitro and in vivo by decreasing proliferation of cells and inducing apoptosis (Wang et al., 2011).

Esophageal Squamous Carcinoma

The anti-neoplastic effects of combinations of anti-cancer drugs (5-fluorouracil, irinotecan and cisplatin) and triterpenes (ursolic acid, betulinic acid, oleanolic acid and a Japanese apricot extract (JAE) containing triterpenes) on esophageal squamous carcinoma cells were examined by the WST-8 (2-(2-methoxy- 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) assay in vitro and by an animal model in vivo. Triterpenes and JAE showed additive and synergistic cytotoxic effects, respectively, on esophageal squamous carcinoma cells (YES-2 cells) by combinational use of 5-fluorouracil. JAE and 5-fluorouracil induced cell-cycle arrest at G2/M phase and at S phase, respectively, and caused apoptosis in YES-2 cells.

These results suggest that triterpenes, especially JAE, are effective supplements for enhancing the chemotherapeutic effect of 5-fluorouracil on esophageal cancer (Yamai et al., 2009).

COX-2 Inhibitor

Subbaramaiah et al. (2000) studied the effects of ursolic acid, a chemo-preventive agent, on the expression of cyclooxygenase-2 (COX-2). Treatment with ursolic acid suppressed phorbol 12-myristate 13-acetate (PMA)-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Ursolic acid also suppressed the induction of COX-2 mRNA by PMA. Increased activator protein-1 activity and the binding of c-Jun to the cyclic AMP response element of the COX-2 promoter, effects were blocked by ursolic acid (Subbaramaiah et al., 2000).

Lung Cancer, Suppresses NF- κB

In terms of general anti-cancer mechanism, ursolic acid has also been found to suppress NF-κB activation induced by various carcinogens through the inhibition of the DNA binding of NF-κB. Ursolic acid also inhibits IκBα kinase and p65 phosphorylation (Shishodia et al., 2003). In particular, ursolic acid has been found to block cell-cycle progression and trigger apoptosis in lung cancer and may hence act as a chemoprevention agent for lung cancer (Hsu et al., 2004).

Breast Cancer

Ursolic acid is a potent inhibitor of MCF-7 cell proliferation. This triterpene exhibits both cytostatic and cytotoxic activity. It exerts an early cytostatic effect at G1 followed by cell death. Results suggest that alterations in cell-cycle phase redistribution of MCF-7 human breast cancer, by ursolic acid, may significantly influence MTT (colorimetric assays) reduction to formazan (Es-Saady et al., 1996).

Induces IL-1 β

Interleukin (IL)-1beta is a pro-inflammatory cytokine responsible for the onset of a broad range of diseases, such as inflammatory bowel disease and rheumatoid arthritis. It has recently been found that aggregated ursolic acid (UA), a triterpene carboxylic acid, is recognized by CD36 for generating reactive oxygen species (ROS) via NADPH oxidase (NOX) activation, thereby releasing IL-1beta protein from murine peritoneal macrophages (pMphi) in female ICR mice. In the present study, Ikeda et al. (2008) investigated the ability of UA to induce IL-1beta production in pMphi from 4 different strains of female mice as well as an established macrophage line. In addition, the different susceptibilities to UA-induced IL-1beta release were suggested to be correlated with the amount of superoxide anion (O2-) generated from the 5 different types of Mphi.

Notably, intracellular, but not extracellular, O2- generation was indicated to play a major role in UA-induced IL-1beta release. Together, these results indicate that the UA-induced IL-1beta release was strain-dependent, and the expression status of CD36 and gp91phox is strongly associated with inducibility.

Induces Apoptosis: Breast Cancer, Prostate Cancer

Ursolic acid (UA) induced apoptosis and modulated glucocorticoid receptor (GR) and Activator Protein-1 (AP-1) in MCF-7 breast cancer cells. UA is a GR modulator and may be considered as a potential anti-cancer agent in breast cancer (Kassi et al., 2009).

UA induces apoptosis via both extrinsic and intrinsic signaling pathways in cancer cells (Kwon et al., 2010). In PC-3 cells, UA inhibits proliferation by activating caspase-9 and JNK as well as FasL activation and Akt inhibition (Zhang et al., 2010). A significant proliferation inhibition and invasion suppression in both a dose- and time-dependent manner is observed in highly metastatic breast cancer MDA-MB-231 cells; this inhibition is related to the down-regulation of MMP2 and u-PA expression (Yeh et al., 2010).

Ursolic acid additionally stimulates the release of cytochrome C in HL-60 cells and breast cancer MCF-7 cells. The activation of caspase-3 in a cytochrome C-dependent manner induces apoptosis via the mitochondrial pathway (Qian et al., 2011).

Colorectal Cancer

Ursolic acid (UA) has strong anti-proliferative and apoptotic effects on human colon cancer HT-29 cells. UA dose-dependently decreased cell proliferation and induced apoptosis, accompanied by activation of caspase 3, 8 and 9. The effects may be mediated by alkaline sphingomyelinase activation (Andersson et al., 2003).

Ursolic acid (UA), using the colorectal cancer (CRC) mouse xenograft model and the HT-29 human colon carcinoma cell line, was evaluated for its efficacy against tumor growth in vivo and in vitro, and its molecular mechanisms were investigated. It was found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation.

These data demonstrate that UA possesses a broad range of anti-cancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment (Lin et al., 2013).

Action: Anti-tumor, inhibits tumor cell migration and invasion

Ursolic acid (UA) is a sort of pentacyclic triterpenoid carboxylic acid purified from natural plant. UA has a series of biological effects such as sedative, anti-inflammatory, anti-bacterial, anti-diabetic, antiulcer, etc. It is discovered that UA has a broad-spectrum anti-tumor effect in recent years, which has attracted more and more scholars’ attention. This review explained anti-tumor actions of UA, including (1) the protection of cells’ DNA from different damages; (2) the anti-tumor cell proliferation by the inhibition of epidermal growth factor receptor mitogen-activated protein kinase signal or of FoxM1 transcription factors, respectively; (3) antiangiogenesis, (4) the immunological surveillance to tumors; (5) the inhibition of tumor cell migration and invasion; (6) the effect of UA on caspase, cytochromes C, nuclear factor kappa B, cyclooxygenase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or mammalian target of rapamycin signal to induce tumor cell apoptosis respectively, and etc. Moreover, UA has selective toxicity to tumor cells, basically no effect on normal cells.

Inhibition of Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Pathway
Activation of mitogen-activated protein kinase (MAPK) allows cell excessive proliferation involved in the carcinogenic process (Park et al., 1999). Subfamilies of MAPK, metastasis.(24) Otherwise, UA suppresses the activation of NF-κB and down-regulation of the MMP-9 protein, which in turn contributes to its inhibitory effects on IL-1β or tumor necrosis factor α (TNF-α)-induced C6 glioma cell invasion (Huang et al., 2009).

U A suppresses inter cellular adhesion molecules-1 (ICAM-1) expression of non-small cell lung cancer (NSCLC) H3255, A549, Calu-6 cells, and significantly inhibits fibronectin expression in a concentration-dependent way. UA significantly suppresses the expression of MMP-9 and MMP-2 and inhibits protein kinase C activity in test cell lines, at the same time, UA reduces cell invasion in a concentration-dependent manner (Huang et al., 2011).

Cancer: Multiple myeloma

Action: Anti-inflammatory, down-regulates STAT3

When dealing with the multiple myeloma, by the way of activating the proto-oncogene-mediated c-Src, JAK1, JAK2, and ERKs, ursolic acid (UA) can not only inhibit the expression of IL-6-induced STAT3 but also downregulates the STAT3 by regulating gene products, such as cyclin D1, Bcl-2, Bcl-xL, surviving, Mcl-1 and VEGF. Above all, UA can inhibit the proliferation of multiple myeloma cells and induce apoptosis, to arrest cells at G1 phase and G0 phase of cell cycle (Pathak et al., 2007).

The essential oils of ginger (Zingiber officinale) and turmeric (Curcuma longa) contain a large variety of terpenoids, some of which possess anticancer, anti-ulcer, and antioxidant properties. Despite their importance, only four terpene synthases have been identified from the Zingiberaceae family: (+)-germacrene D synthase and (S)-β-bisabolene synthase from ginger rhizome, and α-humulene synthase and β-eudesmol synthase from shampoo ginger (Zingiber zerumbet) rhizome (Koo et al., 2012).

Cancer: Colorectal

Wong et al., have previously reported Signal Transducer and Activator of Transcription 3 (STAT3) to be constitutively activated in aldehyde dehydrogenase (ALDH)(+)/cluster of differentiation-133 (CD133)(+) colon cancer-initiating cells. In the present study they tested the efficacy of inhibiting STAT3 signaling in human colon cancer-initiating cells by ursolic acid (UA), which exists widely in fruits and herbs.

ALDH(+)/CD133(+) colon cancer-initiating cells. UA also reduced cell viability and inhibited tumor sphere formation of colon cancer-initiating cells, more potently than two other natural compounds, resveratrol and capsaicin. UA also inhibited the activation of STAT3 induced by interleukin-6 in DLD-1 colon cancer cells. Furthermore, daily administration of UA suppressed HCT116 tumor growth in mice in vivo.

Their results suggest STAT3 to be a target for colon cancer prevention. UA, a dietary agent, might offer an effective approach for colorectal carcinoma prevention by inhibiting persistently activated STAT3 in cancer stem cells.

References

 

Andersson D, Liu JJ, Nilsson A, Duan RD. (2003). Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anti-cancer Research, 23(4):3317-22.

 

Es-Saady D, Simon A, Jayat-Vignoles C, Chulia AJ, Delage C. (1996). MCF-7 cell-cycle arrested at G1 through ursolic acid, and increased reduction of tetrazolium salts. Anti-cancer Research, 16(1):481-6.

 

Hsu YL, Kuo PL, Lin CC. (2004). Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small-cell lung cancer A549 cells. Life Sciences, 75(19), 2303-2316.

 

Ikeda Y, Murakami A, Ohigashi H. (2008). Strain differences regarding susceptibility to ursolic acid-induced interleukin-1beta release in murine macrophages. Life Sci, 83(1-2):43-9. doi: 10.1016/j.lfs.2008.05.001.

 

Kassi E, Sourlingas TG, Spiliotaki M, et al. (2009). Ursolic Acid Triggers Apoptosis and Bcl-2 Down-regulation in MCF-7 Breast Cancer Cells. Cancer Investigation, 27(7):723-733. doi:10.1080/07357900802672712.

 

Kwon SH, Park HY, Kim JY, et al. (2010). Apoptotic action of ursolic acid isolated from Corni fructus in RC-58T/h/SA#4 primary human prostate cancer cells. Bioorg Med Chem Lett, 20:6435–6438. doi: 10.1016/j.bmcl.2010.09.073.

 

Lin J, Chen Y, Wei L, et al. (2013). Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways. Int J Oncol, (4):1235-43. doi: 10.3892/ijo.2013.2040.

 

Liu J. (1995). Pharmacology of oleanolic acid and ursolic acid. Journal of Ethnopharmacology, 49(2), 57-68.

 

Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. (2003). Ursolic Acid Inhibits Nuclear Factor-OE ∫ B Activation Induced by Carcinogenic Agents through Suppression of IOE ∫ BOE± Kinase and p65 Phosphorylation. Cancer Research, 63(15), 4375-4383.

 

Subbaramaiah K, Michaluart P, Sporn MB, Dannenberg AJ. (2000). Ursolic Acid Inhibits Cyclooxygenase-2 Transcription in Human Mammary Epithelial Cells. Cancer Res, 60:2399

 

Qian J, Li X, Guo GY, et al. (2011). Potent anti-tumor activity of emodin on CNE cells in vitro through apoptosis. J Zhejiang Sci-Tech Univ (Chin), 42:756-759

 

Wang X, Zhang F, Yang L, et al. (2011). Ursolic Acid Inhibits Proliferation and Induces Apoptosis of Cancer Cells In Vitro and In Vivo. J Biomed Biotechnol, 2011:419343. doi: 10.1155/2011/419343.

 

Yamai H, et al. (2009). Triterpenes augment the inhibitory effects of anti-cancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo. Int J Cancer, 125(4):952-60. doi: 10.1002/ijc.24433.

 

Yeh CT, Wu CH, Yen GC. (2010). Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol Nutr Food Res, 54:1285–1295. doi: 10.1002/mnfr.200900414.

 

Zhang Y, Kong C, Zeng Y, et al. (2010). Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Mol Carcinog, 49:374–385.

 

Zhang LL, Wu BN, Lin Y et al. (2014) Research Progress of Ursolic Acid’s Anti-Tumor Actions. Chin J Integr Med 2014 Jan;20(1):72-79

 

Reference

 

Huang HC, Huang CY, Lin-Shiau SY, Lin JK. Ursolic acid inhibits IL-1beta or TNF-alpha-induced C6 glioma invasion through suppressing the association ZIP/p62 with PKC-zeta and downregulating the MMP-9 expression. Mol Carcinog 2009;48:517-531

 

Huang CY, Lin CY, Tsai CW, Yin MC. Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. Toxicol In Vitro 2011;25:1274-1280.

 

Park KS, Kim NG, Kim JJ, Kim H, Ahn YH, Choi KY. Differential regulation of MAP kinase cascade in human colorectal tumorigenesis. Br J Cancer 1999;81:1116-1121.

 

 

Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, et al. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res 2007;5:943-595

 

 

Koo HJ, Gang DR. (2012) Suites of terpene synthases explain differential terpenoid production in ginger and turmeric tissues. PLoS One. 2012;7(12):e51481. doi: 10.1371/journal.pone.0051481.

 

 

Wang W, Zhao C, Jou D, Lü J, Zhang C, Lin L, Lin J. (2013) Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3. Anticancer Res. 2013 Oct;33(10):4279-84.

 
Lu C-C, Huang B-R, Liao P-J, Yen G-C. Ursolic acid triggers a non-programmed death (necrosis) in human glioblastoma multiforme DBTRG-05MG cells through MPT pore opening and ATP decline. Molecular Nutrition & Food Research. 2014 DOI: 10.1002/mnfr.201400051

 

 

 

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

Trichosanthin (TCS)

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

Action: Demethylation, anti-tumor immunity, induces apoptosis

Breast

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

Leukemia/Lymphoma, Cervical Cancer, Choriocarcinoma

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

Lung, Anti-tumor Immunity

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

Induce Apoptosis

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

Leukemia

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

Cervical Cancer, Demethylation Activity

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

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

References:

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


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


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


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


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


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

anti-inflammatory, apoptosis, Apoptotic, Camellia sinensis, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, COX-2, induces apoptosis, inflammation, Pro-apoptotic

Theaflavin-2

Cancer: none noted

Action: Anti-inflammatory, induces apoptosis

Apoptosis

Theaflavin-2 (TF-2), a major component of black tea extract (Camellia sinensis [(L.) Kuntze]), induces apoptosis of human colon cancer cells and suppresses serum-induced cyclooxygenase-2 (COX-2) expression 1. The mechanisms of TF-2 for the activation of apoptosis were examined, and the impact on inflammatory genes in a broader panel of cells was evaluated and tested for whether topical anti-inflammatory effects could be observed in vivo. TF-2 triggered apoptosis in five other transformed cancer cell lines, inducing cell shrinkage, membrane blebbing, and mitochondrial clustering within 3 h of treatment. Topical application with TF-2 significantly reduced ear edema and produced a pattern of gene down-regulation similar to that observed in the cell model. These results suggest that the anti-inflammatory and pro-apoptotic activity of TF-2 may be exploited therapeutically in cancer and other diseases associated with inflammation (Gosslau et al., 2011).

Reference

Gosslau A, En Jao DL, Huang MT et al. (2011). Effects of the black tea polyphenol theaflavin-2 on apoptotic and inflammatory pathways in vitro and in vivo. Molecular Nutrition & Food Research, 55(2):198–208. doi: 10.1002/mnfr.201000165

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

Tetrandrine

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

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

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

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

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

Leukemia

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

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

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

MDR, Breast Cancer

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

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

Leukemia, MDR

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

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

Tamoxifen

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

Colon Cancer

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

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

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

Renal Cancer

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

angiogenesis, Anti-cancer, Anti-cancer effect, apoptosis, Chapter 7 Isolates and Cancer Research, induces apoptosis, inhibits angiogenesis, p16, p21, PARP, VEGF, VEGF, XIAP

Teng Long Bu Zhong Tang

Cancer: Colon

Action: Induces apoptosis, inhibits angiogenesis

CT26 colon carcinoma was established in BALB/c mice and treated with Teng Long Bu Zhong Tang (TLBZT), 5-Fu, or TLBZT plus 5-Fu. The tumor volumes were observed. TLBZT significantly inhibited CT26 colon carcinoma growth. TLBZT elicited apoptosis in CT26 colon carcinoma, accompanied by Caspase-3, 8, and 9 activation and PARP cleavage, and down-regulation of XIAP and Survivin. TLBZT also induced cell senescence in CT26 colon carcinoma, with concomitant up-regulation of p16 and p21 and down-regulation of RB phosphorylation.

In addition, angiogenesis and VEGF expression in CT26 colon carcinoma was significantly inhibited by TLBZT treatment. TLBZT exhibited significant anti-cancer effect, and enhanced the effects of 5-Fu in CT26 colon carcinoma, which may correlate with induction of apoptosis and cell senescence, and angiogenesis inhibition (Deng et al., 2013).

Reference

Deng S, Hu B, An HM, et al. (2013). Teng-Long-Bu-Zhong-Tang, a Chinese herbal formula, enhances anti-cancer effects of 5 – Fluorouracil in CT26 colon carcinoma. BMC Complement Altern Med, 13:128. doi: 10.1186/1472-6882-13-128.

anti-proliferative, apoptosis, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, induces apoptosis, Rectal cancer

Steamed American Ginseng Berry Ginsenosides

Cancer: Colorectal cancer

Action: Cell-cycle arrest, induces apoptosis

Research

The steaming of American ginseng berries augments ginsenoside Rg3 content and increases the anti-proliferative effects on two human colorectal cancer cell lines (Wang et al., 2006).

It has been found to inhibit the colorectal cancer growth both in vitro and in vivo, and the mechanism of this inhibition is likely through cell-cycle arrest and induced apoptosis in the cells (Xie et al., 2009).

References

Wang CZ, Zhang B, Song WX, Wang A, Ni M, Luo X, et al. (2006). Steamed American Ginseng Berry:,Äâ Ginsenoside Analyzes and Anti-cancer Activities. Journal of Agricultural and Food Chemistry, 54(26): 9936-9942.


Xie JT, Wang CZ, Zhang B, Mehendale SR, Li XL, Sun S, et al. (2009). In Vitro and in Vivo Anti-cancer Effects of American Ginseng Berry: Exploring Representative Compounds. Biological and Pharmaceutical Bulletin, 32(9):1552-1558.

apoptosis, Chapter 7 Isolates and Cancer Research, induces apoptosis, MDR, P-gp

Solanum incanum, solamargine alkaloid

Cancer: Squamous cell

Action: Apoptosis

Solanum incanum is nightshade native to Sub-Saharan Arica and the Middle East.

SR-T100, extracted from the Solanum incanum, contains solamargine alkaloid as the main active ingredient. Thirteen patients, who suffered with 14 actinic keratoses (AKs) were treated with once-daily topical SR-T100 gel and 10 AKs cured after 16 weeks, showing negligible discomforts. Our studies indicate that SR-T100 induces apoptosis of SCC cells via death receptors and the mitochondrial death pathway. The high efficacy of SR-T100 in these preclinical trials suggests that SR-T100 is a highly promising herb for AKs and related disorders (Wu et al., 2011).

Induces Apoptosis

Solamargine (SM), a steroidal glycoalkaloid isolated from the Chinese herb Solanum incanum, has been shown to inhibit the growth of some cancer cell lines and induce significant apoptosis.

SM at concentrations that induce P-gp down-regulation triggered cytotoxicity and apoptosis in MDR K562/A02 cells (Li et al., 2011).

References

Li X, Zhao Y, Ji M, Liu SS, et al. (2011). Induction of actin disruption and down-regulation of P-glycoprotein expression by solamargine in Multi-drug-resistant K562/A02 cells. Chin Med J, 124(13):2038-2044


Wu CH, Liang CH, Shiu LY, et al. (2011). Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway. J Dermatol Sci, 63(2):83-92.


Yu M, Liu X, Xu B, et al. (2008). Mechanism reversing MDR of K562/A02 by garlicin combined with erythromycin. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 16(5):1044-9.

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

Salvianolic acid-B / Salvinal

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

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

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

Anti-cancer/MDR

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

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

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

Glioma

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

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

Reduced Cardiotoxicity

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

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

Oral Cancer

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

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

Head and Neck Cancer

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

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

Inflammatory-associated tumor development

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

Squamous Cell Carcinoma

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

References

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


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


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


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


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


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


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


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

Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, AP-1, apoptosis, BAX, Bcl-2, c-Fos, c-Jun, c-Myc, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, cytotoxic, ERK, G0/G1, G1, G2/M, IAP, IKK, IL-2, IL-6, Immune, Immunomodulatory, induces apoptosis, Lung cancer, Ovarian cancer, p16, p21, p53, PARP, pro-oxidative, Radio-sensitizer, radio-sensitizing, ROS, TIMP-2, TNF, XIAP

Saikosaponin

Cancers:
Cervical, colon, liver, lung, ovarian, liver, breast, hepatocellular

Action: Anti-angiogenic, anti-metastatic, chemo-sensitizer, pro-oxidative, cell-cycle arrest

T cell-mediated autoimmune, induces apoptosis, immune regulating, radio-sensitizer

Induces Apoptosis

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

Annexin V immunofluorescence detection, DNA fragmentation assays and FACScan analysis of propidium iodide-staining cells showed that gentiopicroside, baicalein, and geniposide had little effect, whereas alisol B acetate and saikosaponin-d profoundly induced apoptosis in Hep3B cells. Alisol B acetate, but not saikosaponin-d, induced G2/M arrest of the cell-cycle as well as a significant increase in caspase-3 activity. 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).

Breast

Saikosaponin-A treatment of MDA-MB-231 for 3 hours and of MCF-7 cells for 2 hours, respectively, caused an obvious increase in the sub G1 population of cell-cycles.

Apoptosis in MDA-MB-231 cells was independent of the p53/p21 pathway mechanism and was accompanied by an increased ratio of Bax to Bcl-2 and c-myc levels and activation of caspase-3. In contrast, apoptosis of MCF-7 cells may have been initiated by the Bcl-2 family of proteins and involved p53/p21 dependent pathway mechanism, and was accompanied by an increased level of c-myc protein. The apoptosis of both MDA-MB-231 and MCF-7 cells showed a difference worthy of further research (Chen, Chang, Chung, & Chen, 2003).

Hepatocellular Carcinoma

The signaling pathway mediating induction of p15(INK4b) and p16(INK4a) during HepG2 growth inhibition triggered by the phorbol ester tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) and the Chinese herbal compund Saikosaponin A was investigated.

Expressions of proto-oncogene c-jun, junB and c-fos were induced by TPA and Saikosaponin A between 30 minutes to 6 hours of treatment. Pre-treatment of 20 microg/ml PD98059, an inhibitor of MEK (the upstream kinase of ERK), prevents the TPA and Saikosaponin A triggered HepG2 growth inhibition by 50% and 30%, respectively. In addition, AP-1 DNA-binding assay, using non-isotopic capillary electrophoresis and laser-induced fluorescence (CE/LIF), demonstrated that the AP-1-related DNA-binding activity was significantly induced by TPA and Saikosaponin A, which can be reduced by PD98059 pre-treatment.

Results suggest that activation of ERK, together with its downstream transcriptional machinery, mediated p15(INK4b) and p16(INK4a) expression that led to HepG2 growth inhibition (Wen-Sheng, 2003).

The effects of Saikosaponin D (SSd) on syndecan-2, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in livers of rats with hepatocellular carcinoma (HCC) was investigated.

The model group had more malignant nodules than the SSd group. Model-group HCC cells were grade III; SSd-group HCC cells were grades I-II. Controls showed normal hepatic cell phenotypes and no syndecan-2+ staining. Syndecan-2+ staining was greater in the model group (35.2%, P < or = 0.001) than in controls or the SSd group (16.5%, P < or = 0.001). The model group had more intense MMP-2+ staining than controls (0.37 vs 0.27, P< or =0.01) or the SSd group (0.31 vs 0.37, P< or =0.05); and higher MMP-13+ staining (72.55%) than in controls (12.55%, P< or =0.001) and SSd group (20.18%, P< or =0.01).

The model group also had more TIMP-2+ staining (57.2%) than controls (20.9%, P< or =0.001) and SSd group (22.7%, P< or=0.001). Controls and SSd group showed no difference in TIMP-2+ rates.

SSd inhibited HCC development, and downregulated expression of syndecan-2, MMP-2, MMP-13 and TIMP-2 in rat HCC liver tissue (Jia et al., 2012).

T Cell-mediated Autoimmune

Saikosaponin-d (Ssd) is a triterpene saponin derived from the medicinal plant, Bupleurum falcatum L. (Umbelliferae). Previous findings showed that Ssd exhibits a variety of pharmacological and immunomodulatory activities including anti-inflammatory, anti-bacterial, anti-viral and anti-cancer effects.

Results demonstrated that Ssd not only suppressed OKT3/CD28-costimulated human T cell proliferation, it also inhibited PMA, PMA/Ionomycin and Con A-induced mouse T cell activation in vitro. The inhibitory effect of Ssd on PMA-induced T cell activation was associated with down-regulation of NF-kappaB signaling through suppression of IKK and Akt activities. In addition, Ssd suppressed both DNA binding activity and the nuclear translocation of NF-AT and activator protein 1 (AP-1) of the PMA/Ionomycin-stimulated T cells. The cell surface markers, such as IL-2 receptor (CD25), were also down-regulated along with decreased production of pro-inflammatory cytokines of IL-6, TNF-alpha and IFN-gamma.

Results indicate that the NF-kappaB, NF-AT and AP-1 (c-Fos) signaling pathways are involved in the T cell inhibition evoked by Ssd. Ssd could be a potential candidate for further study in treating T cell-mediated autoimmune conditions (Wong, Zhou, Cheung, Li, & Liu, 2009).

Cervical Cancer

Saikosaponin-a and -d, two naturally occurring compounds derived from Bupleurum radix, have been shown to exert anti-cancer activity in several cancer cell lines. However, the effect of a combination of saikosaponins with chemotherapeutic drugs have never been addressed. Investigated as to whether these two saikosaponins have chemo-sensitization effect on cisplatin-induced cancer cell cytotoxicity was carried out.

Two cervical cancer cell lines, HeLa and Siha, an ovarian cancer cell line, SKOV3, and a non-small-cell lung cancer cell line, A549, were treated with saikosaponins or cisplatin individually or in combination. Cell death was quantitatively detected by the release of lactate dehydrogenase (LDH) using a cytotoxicity detection kit. Cellular ROS was analyzed by flow cytometry. Apoptosis was evaluated by AO/EB staining, flow cytometry after Anexin V and PI staining, and Western blot for caspase activation. ROS scavengers and caspase inhibitor were used to determine the roles of ROS and apoptosis in the effects of saikosaponins on cisplatin-induced cell death.

Both saikosaponin-a and -d sensitized cancer cells to cisplatin-induced cell death in a dose-dependent manner, which was accompanied with induction of reactive oxygen species (ROS) accumulation.

Results suggest that saikosaponins sensitize cancer cells to cisplatin through ROS-mediated apoptosis, and the combination of saikosaponins with cisplatin could be an effective therapeutic strategy (Wang et al., 2010).

Colon Cancer

Saikosaponin-a (SSa)-induced apoptosis of HCC cells was associated with proteolytic activation of caspase-9, caspase-3, and PARP cleavages and decreased levels of IAP family members, such as XIAP and c-IAP-2, but not of survivin. SSa treatment also enhanced the activities of caspase-2 and caspase-8, Bid cleavage, and the conformational activation of Bax. Moreover, inhibition of caspase-2 activation by the pharmacological inhibitor z-VDVAD-fmk, or by knockdown of protein levels using a si-RNA, suppressed SSa-induced caspase-8 activation, Bid cleavage, and the conformational activation of Bax. Although caspase-8 is an initiator caspase like caspase-2, the inhibition of caspase-8 activation by knockdown using a si-RNA did not suppress SSa-induced caspase-2 activation.

Results suggest that sequential activation of caspase-2 and caspase-8 is a critical step in SSa-induced apoptosis (Kim & Hong, 2011).

Immune Regulating

Tumor necrosis factor-alpha (TNF- α ) was reported as an anti-cancer therapy due to its cytotoxic effect against an array of tumor cells. However, its undesirable responses of TNF- α on activating NF- κB signaling and pro-metastatic property limit its clinical application in treating cancers. Therefore, sensitizing agents capable of overcoming this undesirable effect must be valuable for facilitating the usage of TNF- α -mediated apoptosis therapy for cancer patients. Previously, saikosaponin-d (Ssd), a triterpene saponin derived from the medicinal plant, Bupleurum falcatum L. (Umbelliferae), exhibited a variety of pharmacological activities such as anti-inflammatory, anti-bacterial, anti-viral and anti-cancer.

Investigation found that Ssd could potentially inhibit activated T lymphocytes via suppression of NF- κ B, NF-AT and AP-1 signaling. Ssd significantly potentiated TNF- α -mediated cell death in HeLa and HepG2 cancer cells via suppression of TNF- α -induced NF- κ B activation and its target genes expression involving cancer cell proliferation, invasion, angiogenesis and survival. Also, Ssd revealed a significant potency in abolishing TNF- α -induced cancer cell invasion and angiogenesis in HUVECs while inducing apoptosis via enhancing the loss of mitochondrial membrane potential in HeLa cells.

Collectively, findings indicate that Ssd has significant potential to be developed as a combined adjuvant remedy with TNF- α for cancer patients (Wong et al., 2013).

Radio-sensitizer

Saikosaponin-d (SSd), a monomer terpenoid purified from the Chinese herbal drug Radix bupleuri, has multiple effects, including anti-cancer properties. Treatment with SSd alone and radiation alone inhibited cell growth and increased apoptosis rate at the concentration used. These effects were enhanced when SSd was combined with radiation. Moreover, SSd potentiated the effects of radiation to induce G0/G1 arrest in SMMC-7721 hepatocellular carcinoma cells, and reduced the G2/M-phase population under hypoxia. SSd potentiates the effects of radiation on SMMC-7721 cells; thus, it is a promising radio-sensitizer. The radio-sensitizing effect of SSd may contribute to its effect on the G0/G1 and G2/M checkpoints of the cell-cycle (Wang et al., 2013).

References

Chen JC, Chang NW, Chung JG, Chen KC. (2003). Saikosaponin-A induces apoptotic mechanism in human breast MDA-MB-231 and MCF-7 cancer cells. The American Journal of Chinese Medicine, 31(3), 363-77.


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.


Jia X, Dang S, Cheng Y, et al. (2012). Effects of saikosaponin-d on syndecan-2, matrix metalloproteinases and tissue inhibitor of metalloproteinases-2 in rats with hepatocellular carcinoma. Journal of Traditional Chinese Medicine, 32(3), 415-22.


Kim BM, Hong SH. (2011). Sequential caspase-2 and caspase-8 activation is essential for saikosaponin a-induced apoptosis of human colon carcinoma cell lines. Apoptosis, 16(2), 184-197. doi: 10.1007/s10495-010-0557-x.


Wang BF, Dai ZJ, Wang XJ, et al. (2013). Saikosaponin-d increases the radiosensitivity of smmc-7721 hepatocellular carcinoma cells by adjusting the g0/g1 and g2/m checkpoints of the cell-cycle. BMC Complementary and Alternative Medicine, 13:263. doi:10.1186/1472-6882-13-263


Wang Q, Zheng XL, Yang L, et al. (2010). Reactive oxygen species-mediated apoptosis contributes to chemo-sensitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells. Journal of Experimental & Clinical Cancer Research, 9(29), 159. doi: 10.1186/1756-9966-29-159.


Wen-Sheng, W. (2003). ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin A. Oncogene, 22(7), 955-963.


Wong VK, Zhang MM, Zhou H, et al. (2013). Saikosaponin-d Enhances the Anti-cancer Potency of TNF- α via Overcoming Its Undesirable Response of Activating NF-Kappa B Signaling in Cancer Cells. Evidence-based Complementary and Alternative Medicine, 2013(2013), 745295. doi: 10.1155/2013/745295.


Wong VK, Zhou H, Cheung SS, Li T, Liu L. (2009). Mechanistic study of saikosaponin-d (Ssd) on suppression of murine T lymphocyte activation. Journal of Cellular Biochemistry, 107(2), 303-15. doi: 10.1002/jcb.22126.

ABC, Anti-cancer, anti-inflammatory, apoptosis, apoptosis-inducing, Apoptotic, autophagic cell death, Autophagy, BAX, Breast cancer, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, chemo-preventive activity, Chemo-preventive effects, Chemoprevention, Chemotherapy, chemotherapy-induced cytotoxicity, Colon Cancer or Colorectal cancer, enhances chemo-sensitivity, ER, Fibrosarcoma, induces apoptosis, Lung cancer, Lymphoma, MDR, Melanoma, Multi-Drug Resistance, Multi-drug resistance, Neuroblastoma, Pancreatic cancer, Pro-apoptotic, Prostate cancer, Radio-sensitizer, radiotherapy, ROS, Sarcoma, Skin cancer, TRAIL

Resveratrol 98%

Cancer:
Breast, lymphoma, breast, gastric, colorectal, esophageal, prostate, pancreatic, leukemia, skin, lung

Action: Chemoprevention, anti-inflammatory, MDR, chemotherapy-induced cytotoxicity, radio-sensitizer, enhances chemo-sensitivity

Resveratrol (RSV) is a phytoalexin found in food products including berries and grapes, as well as plants (including Fallopia japonica (Houtt.), Gnetum cleistostachyum (C. Y. Cheng), Vaccinium arboretum (Marshall), Vaccinium angustifolium (Aiton) and Vaccinium corymbosum (L.)

Although resveratrol is ubiquitous in nature, it is found in a limited number of edible substances, most notably in grapes. In turn, due to the peculiar processing methodology, resveratrol is found predominantly in red wines. Thus, resveratrol received intense and immediate attention. A large number of resveratrol anti-cancer activities were reported, affecting all the steps of cancerogenesis, namely initiation, promotion, and progression. Thereafter, an exponential number of reports on resveratrol accumulated and, so far, more than 5,000 studies have been published (Borriello et al., 2014).

Up to the end of 2011, more than 50 studies analyzed the effect of resveratrol as an anti-cancer compound in animal models of different cancers, including skin cancer (non-melanoma skin cancer and melanoma); breast, gastric, colorectal, esophageal, prostate, and pancreatic cancers; hepatoma, neuroblastoma, fibrosarcoma, and leukemia (Ahmad et al., 2004; Hayashibara et al., 2002; Pozo-Guisado et al., 2005; Mohan et al., 2006; Tang et al., 2006). In general, these preclinical studies suggest a positive activity of the molecule in lowering the progression of cancer, reducing its dimension, and decreasing the number of metastases (Vang et al., 2011).

Breast

Resveratrol was shown to have cancer chemo-preventive activity in assays representing three major stages of carcinogenesis. It has been found to mediate anti-inflammatory effects and inhibit cyclooxygenase and hydroperoxidase functions (anti-promotion activity). It has also been found to inhibit the development of pre-neoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model (Jang et al., 1997).

In addition, resveratrol, a partial ER agonist itself, acts as an ER antagonist in the presence of estrogen leading to inhibition of human breast cancer cells (Lu et al., 1999).

Besides chemo-preventive effects, resveratrol appears to exhibit therapeutic effects against cancer itself. Limited data in humans have revealed that RSV is pharmacologically safe (Aggarwal et al., 2004).

Chemotherapy-Induced Cytotoxicity

RSV markedly enhanced Dox-induced cytotoxicity in MCF-7/adr and MDA-MB-231 cells. Treatment with a combination of RSV and Dox significantly increased the cellular accumulation of Dox by down-regulating the expression levels of ATP-binding cassette (ABC) transporter genes, MDR1, and MRP1. Further in vivo experiments in the xenograft model revealed that treatment with a combination of RSV and Dox significantly inhibited tumor volume by 60%, relative to the control group.

These results suggest that treatment with a combination of RSV and Dox would be a helpful strategy for increasing the efficacy of Dox by promoting an intracellular accumulation of Dox and decreasing multi-drug resistance in human breast cancer cells (Kim et al., 2013).

Radio-sensitizer/Lung Cancer

Previous studies indicated that resveratrol (RV) may sensitize tumor cells to chemotherapy and ionizing radiation (IR). However, the mechanisms by which RV increases the radiation sensitivity of cancer cells have not been well characterized. Here, we show that RV treatment enhances IR-induced cell killing in non-small-cell lung cancer (NSCLC) cells through an apoptosis-independent mechanism. Further studies revealed that the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive senescent cells was markedly higher in cells treated with IR in combination with RV compared with cells treated either with IR or RV alone, suggesting that RV treatment enhances IR-induced premature senescence in lung cancer cells.

Collectively, these results demonstrate that RV-induced radio-sensitization is associated with significant increase of ROS production, DNA-DSBs and senescence induction in irradiated NSCLC cells, suggesting that RV treatment may sensitize lung cancer cells to radiotherapy via enhancing IR-induced premature senescence (Luo et al., 2013).

Lymphoma

Ko et al. (2011) examined the effects of resveratrol on the anaplastic large-cell lymphoma (ALCL) cell line SR-786. Resveratrol inhibited growth and induced cellular differentiation, as demonstrated by morphological changes and elevated expression of T cell differentiation markers CD2, CD3, and CD8. Resveratrol also triggered cellular apoptosis, as demonstrated by morphological observations, DNA fragmentation, and cell-cycle analyzes. Further, the surface expression of the death receptor Fas/CD95 was increased by resveratrol treatment. Our data suggest that resveratrol may have potential therapeutic value for ALCL.

Skin Cancer

Treatment with combinations of resveratrol and black tea polyphenol (BTP) also decreased expression of proliferating cell nuclear antigen in mouse skin tissues/tumors than their solitary treatments as determined by immunohistochemistry. In addition, histological and cell death analysis also confirmed that resveratrol and BTP treatment together inhibits cellular proliferation and markedly induces apoptosis. Taken together, results for the first time lucidly illustrate that resveratrol and BTP in combination impart better suppressive activity than either of these agents alone and accentuate that development of novel combination therapies/chemo-prevention using dietary agents will be more beneficial against cancer (George et al., 2011).

Prostate Cancer

Resveratrol-induced ROS production, caspase-3 activity and apoptosis were inhibited by N-acetylcysteine. Bax was a major pro-apoptotic gene mediating the effects of resveratrol as Bax siRNA inhibited resveratrol-induced apoptosis. Resveratrol enhanced the apoptosis-inducing potential of TRAIL, and these effects were inhibited by either dominant negative FADD or caspase-8 siRNA. The combination of resveratrol and TRAIL enhanced the mitochondrial dysfunctions during apoptosis. These properties of resveratrol strongly suggest that it could be used either alone or in combination with TRAIL for the prevention and/or treatment of prostate cancer (Shankar et al., 2007).

Breast Cancer

Scarlatti et al. (2008) demonstrate that resveratrol acts via multiple pathways to trigger cell death, induces caspase-dependent and caspase-independent cell death in MCF-7 casp-3 cells, induces only caspase-independent cell death in MCF-7vc cells, and stimulates macroautophagy. Using BECN1 and hVPS34 (human vacuolar protein sorting 34) small interfering RNAs, they demonstrated that resveratrol activates Beclin 1-independent autophagy in both cell lines, whereas cell death via this uncommon form of autophagy occurs only in MCF-7vc cells. They also show that this variant form of autophagic cell death is blocked by the expression of caspase-3, but not by its enzymatic activity. In conclusion, this study reveals that non-canonical autophagy induced by resveratrol can act as a caspase-independent cell death mechanism in breast cancer cell.

References

Aggarwal BB, Bhardwaj A, Aggarwal RS et al. (2004). Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies. Anti-cancer Research, 24(5A): 2783-2840.


Ahmad KA, Clement MV, Hanif IM, et al (2004). Resveratrol inhibits drug-induced apoptosis in human leukemia cells by creating an intracellular milieu nonpermissive for death execution. Cancer Res, 64:1452–1459


Borriello A, Bencivenga D, Caldarelli I, et al. (2014). Resveratrol: from basic studies to bedside. Cancer Treat Res, 159:167-84. doi: 10.1007/978-3-642-38007-5_10.


George J, Singh M, Srivastava AK, et al (2011). Resveratrol and black tea polyphenol combination synergistically suppress mouse skin tumors growth by inhibition of activated MAPKs and p53. PLoS ONE, 6:e23395


Hayashibara T, Yamada Y, Nakayama S, et al (2002). Resveratrol induces down-regulation in survivin expression and apoptosis in HTLV-1-infected cell lines: a prospective agent for adult T cell leukemia chemotherapy. Nutr Cancer, 44:193–201


Jang M, Cai L, Udeani GO, et al. (1997). Cancer Chemo-preventive Activity of Resveratrol, a Natural Product Derived from Grapes. Science, 275(5297):218-220.


Kim TH, Shin YJ, Won AJ, et al. (2013). Resveratrol enhances chemosensitivity of doxorubicin in Multi-drug-resistant human breast cancer cells via increased cellular influx of doxorubicin. Biochim Biophys Acta, S0304-4165(13)00463-7. doi: 10.1016/j.bbagen.2013.10.023.


Ko YC, Chang CL, Chien HF, et al (2011). Resveratrol enhances the expression of death receptor Fas/CD95 and induces differentiation and apoptosis in anaplastic large-cell lymphoma cells. Cancer Lett, 309:46–53


Lu R, Serrero G. (1999). Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. Journal of Cellular Physiology, 179(3):297-304.


Luo H, Wang L, Schulte BA, et al. (2013). Resveratrol enhances ionizing radiation-induced premature senescence in lung cancer cells. Int J Oncol, 43(6):1999-2006. doi: 10.3892/ijo.2013.2141.


Mohan J, Gandhi AA, Bhavya BC, et al. (2006). Caspase-2 triggers Bax-Bak-dependent and – independent cell death in colon cancer cells treated with resveratrol. J Biol Chem, 281:17599–17611


Pozo-Guisado E, Merino JM, Mulero-Navarro S, et al. (2005). Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with down-regulation of Bcl-2 and NF-kappaB. Int J Cancer, 115:74–84.


Scarlatti F, Maffei R, Beau I, et al (2008). Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ, 8:1318–1329


Shankar S, Siddiqui I, Srivastava RK. (2007). Molecular mechanisms of resveratrol (3,4,5- trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. Mol Cell Biochem, 304:273–285


Tang HY, Shih A, Cao HJ, et al. (2006). Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. Mol Cancer Ther, 5:2034–2042


Vang O, Ahmad N, Baile CA, et al. (2011). What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS ONE, 6:e19881

AMPK, Anti-cancer, AP-1, apoptosis, aromatase inhibition, BAX, Bcl-2, Breast cancer, c-Jun, c-Myc, cAMP, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemotherapy, Colon Cancer or Colorectal cancer, Down-regulates, Endometrial cancer, G1, G2/M, HS578T, MDA-MB-231, MCF-7, HT-29, induces apoptosis, MCF-7/ADR, MDR, Multi-Drug Resistance, Multi-drug resistance, PR, Pueraria lobata, Rectal cancer, S

Puerarin

Cancer: Colon, breast, acute myeloid leukemia

Action: MDR, aromatase inhibition, induces apoptosis

Induces Apoptosis, Colorectal Cancer

Puerarin is isolated from Pueraria radix (Pueraria lobata [(Willd.) Ohwi]) and has beneficial effects on cardiovascular, neurological, and hyperglycemic disorders, as well as anti-cancer properties. Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has anti-thrombotic and anti-allergic properties and stimulates estrogenic activity.

Methyl thiazolyl tetrazolium assay (MTT) assay revealed a dose-dependent reduction of HT-29 cellular growth in response to puerarin treatment. Apoptosis was observed following treatments with ³ 25µM puerarin, as reflected by the appearance of the subdiploid fraction and NDA fragmentations. Puerarin also affects the expression of apoptosis-associated genes, revealing an increase of bax and decreases of c-myc and bcl-2.

Finally, puerarin treatment significantly increased the activation of caspase-3, a key executioner of apoptosis. These findings indicate that puerarin may act as a chemo-preventive and/or chemotherapeutic agent in colon cancer cells by reducing cell viability and inducing apoptosis (Li, et al., 2006).

Induces Apoptosis, Breast Cancer

Puerarin exhibits a dose-dependent inhibition of cell growth in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell-cycle distribution and apoptosis assays revealed that puerarin induced cell apoptosis through a caspase-3-dependent pathway and mediated cell-cycle arrest in the G2/M phase. It is therefore suggested that puerarin may act as a chemo-preventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis (Lin et al., 2009).

Breast Cancer, MDR

Purearin down-regulates MDR1 expression in MCF-7/adriamycin (MCF-7/adr), a human breast MDR cancer cell line. Multi-drug resistance (MDR) is a major obstacle in cancer chemotherapy and its inhibition is an effective way to reverse cancer drug resistance. Puerarin treatment significantly inhibited MDR1 expression, MDR1 mRNA and MDR1 promoter activity in MCF-7/adr cells. The suppression of MDR1 was accompanied by partial recovery of intracellular drug accumulation, leading to increased toxicity of adriamycin and fluorescence of rhodamine 123, indicating that puerarin reversed the MDR phenotype by inhibiting the drug efflux function of MDR1. Puerarin stimulated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase and glycogen synthase kinase-3beta phosphorylation, but puerarin decreased cAMP-responsive element-binding protein phosphorylation.

The puerarin-induced suppression of MDR1 expression was reduced by AMPK inhibitor (compound C). Furthermore, both MDR1 protein expression and the transcriptional activity of cAMP-responsive element (CRE) were inhibited by puerarin and protein kinase A/CRE inhibitor (H89). Taken together, these results suggested that puerarin down-regulated MDR1 expression via nuclear factor kappa-B and CRE transcriptional activity-dependent up-regulation of AMPK in MCF-7/adr cells (Hien et al., 2010).

Acute Myeloid Leukemia (AML)

The results showed that a certain concentration of puerarin (PR) could inhibit the proliferation of these four cell lines effectively in time-and dose-dependent manners, and the intensity of inhibition on four kinds of acute myeloid leukemia (AML) cell lines was from high to low as follows: NB4>Kasumi-1>U937>HL-60. Meanwhile, PR could also change cycle process, cell proportion in G1/G0 phase decreased, cells in S phase increased and Sub-diploid peak also appeared. It is concluded that PR can selectively inhibit the proliferation of four AML cell lines and block cell-cycle process, especially for NB4 cells (Shao et al., 2010).

Aromatase Inhibition

Aromatase P450 (P450 (arom)) is overexpressed in endometriosis, endometrial cancers and uterine fibroids. With weak estrogen agonists/antagonists and some other enzymatic activities, isoflavones are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. Puerarin is a major isoflavonoid compound isolated from Pueraria lobata (ge gen).

Yu et al. (2008) found that puerarin exerted a time-course effect on the inhibition of c-jun mRNA, which parallelled that of P450(arom). The suppression of P450(arom) expression and activity by puerarin treatment may associate with the down-regulation of transcription factor AP-1 or c-jun.

References

Hien TT, Kim HG, Han EH, Kang KW, Jeong HG. (2010). Molecular mechanism of suppression of MDR1 by puerarin from Pueraria lobata via NF- κ B pathway and cAMP-responsive element transcriptional activity-dependent up-regulation of AMP-activated protein kinase in breast cancer MCF-7/adr cells. Mol Nutr Food Res, 54(7):918-28. doi: 10.1002/mnfr.200900146.


Lin YJ, Hou YC, Lin CH, et al. (2009). Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells. Biochemical and Biophysical Research Communications, 378(4):683-8. doi:10.1016/j.bbrc.2008.10.178


Shao HM, Tang YH, Jiang PJ, et al. (2010). Inhibitory effect of flavonoids of puerarin on proliferation of different human acute myeloid leukemia cell lines in vitro. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 18(2):296-9.


Yu C, Li Y, Chen H, Yang S, Xie G. (2008). Decreased expression of aromatase in the Ishikawa and RL95-2 cells by the isoflavone, puerarin, is associated with inhibition of c-jun expression and AP-1 activity. Food Chem Toxicol, 46(12):3671-6. doi: 10.1016/j.fct.2008.09.045.


Yu Z, Li WJ. (2006). Induction of apoptosis by puerarin in colon cancer HT-29 cells. Cancer Letters, 238(1):53-60.

apoptosis, cancer stem cells, Chapter 7 Isolates and Cancer Research, CSC, CSCs, EMT, induces apoptosis

Pterostilbene

Cancer: Liver

Action: Induces apoptosis, cancer stem cells

Induces Apoptosis

Pterostilbene (PT) extracted from blueberries dose-dependently reduced the enrichment of CD133 (+) Mahlavu cells upon irradiation; PT treatment also prevented tumor sphere formation, reduced stemness gene expression, and suppressed invasion and migration abilities as well as increasing apoptosis of CD133 (+) Mahlavu CSCs (Lee et al., 2013).

CSCs

PT effectively suppresses the generation of CSCs and metastatic potential under the influence of M2 TAMs via modulating EMT associated signaling pathways, specifically NF-κB/miR488 circuit. Thus, PT could be an ideal anti-CSC agent in clinical settings (Mak et al., 2013).

References

Lee CM, Su YH, Huynh TT, et al. (2013). BlueBerry Isolate, Pterostilbene, Functions as a Potential Anti-cancer Stem Cell Agent in Suppressing Irradiation-Mediated Enrichment of Hepatoma Stem Cells. Evid Based Complement Alternat Med, 2013:258425. doi: 10.1155/2013/258425.


Mak KK, Wu AT, Lee WH, et al. (2013). Pterostilbene, a bioactive component of blueberries, suppresses the generation of breast cancer stem cells within tumor microenvironment and metastasis via modulating NF-κ B/microRNA 448 circuit. Mol Nutr Food Res, 57(7):1123-34. doi: 10.1002/mnfr.201200549.

anti-inflammatory, anti-oxidant, anxiolytic, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, COX-2, COX-2 down-regulation, FasL, G0/G1, G1, Gastric cancer or Stomach cancer, growth-inhibitory, HT-29, IL-1, IL-6, induces apoptosis, inflammation, Nitric Oxide, p27, Paeonia suffruticosa, S, TNF

Paenol

Cancer: Gastric

Action: Attenuates nephrotoxicity, anti-inflammatory, anti-oxidant, inhibits TNF- α , induces apoptosis, COX-2 down-regulation

Inhibits TNF- α

Moutan Cortex, the root bark of Paeonia suffruticosa Andrews, has been used extensively as a traditional medicine for treatment of various diseases such as atherosclerosis, infection, and inflammation. Previous studies have revealed that the extracts of Moutan Cortex can inhibit nitric oxide and TNF- α in activated mouse peritoneal macrophages (Chung et al., 2007).

A variety of compounds including paeonoside, paeonolide, apiopaeonoside, paeoniflorin, oxypaeoniflorin, benzoyloxypaeoniflorin, benzoylpaeoniflorin, paeonol, and sugars have been identified in Moutan Cortex (Chen et al., 2006).

Attenuates Nephrotoxicity

Paeonol, a major compound of Moutan Cortex, has been found to attenuate cisplatin-induced nephrotoxicity in mice. Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug.

Balb/c mice (6 to 8  w of age, weighing 20 to 25  g) were administered with Moutan Cortex (300  mg/kg) or paeonol (20 mg/kg) once a day. At day 4, mice received cisplatin (30, 20, or 10   mg/kg) intraperitoneally.

The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of pro-inflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin (Lee et al., 2013).

Paeonol, a major phenolic component of Moutan Cortex, has various biological activities such as anti-aggregatory, anti-oxidant, anxiolytic-like, and anti-inflammatory functions (Ishiguro et al., 2006). In this study, paeonol treatment significantly reduced the elevated levels of serum creatinine and BUN. In addition, the role of pro-inflammatory cytokines in cisplatin-induced acute renal failure has been well documented (Faubel et al., 2007; Ramesh & Reeves, 2002), and elevation of the pro-inflammatory cytokines TNF-α and IL-1β as well as that of IL-6 has been demonstrated in humans with acute renal failure (Simmons et al., 2004).

Apoptosis-inducing & Gastric Cancer

Paeonol has significantly growth-inhibitory and apoptosis-inducing effects in gastric cancer cells both in vitro and in vivo. In vitro, paeonol caused dose-dependent inhibition on cell proliferation and induced apoptosis. Cell cycle analysis revealed a decreased proportion of cells in G0/G1 phase, with arrest at S. Paeonol treatment in gastric cancer cell line MFC and SGC-790 cells significantly reduced the expression of Bcl-2 and increased the expression of Bax in a concentration-related manner. Administration of paeonol to MFC tumor-bearing mice significantly lowered the tumor growth and caused tumor regression (Li et al., 2010).

COX-2 Down-regulation

One of the apoptotic mechanisms of paeonol is down-regulation of COX-2. p27 is up-regulated simultaneously and plays an important part in controlling cell proliferation and is a crucial factor in the Fas/FasL apoptosis pathway. Cell proliferation was inhibited by different concentrations of paeonol. By immunocytochemical staining, Ye et al. (2009) found that HT-29 cells treated with paeonol (0.024-1.504 mmol/L) reflected reduced expression of COX-2 and increased expression of p27 in a dose-dependent manner. RT-PCR showed that paeonol down-regulated COX-2 and up-regulated p27 in a dose- and time-dependent manner in HT-29 cells.

References

Chen G, Zhang L, Zhu Y. (2006). Determination of glycosides and sugars in moutan cortex by capillary electrophoresis with electrochemical detection. Journal of Pharmaceutical and Biomedical Analysis, 41(1):129–134.


Chung HS, M. Kang, C. Cho et al. (2007). Inhibition of nitric oxide and tumor necrosis factor-alpha by moutan cortex in activated mouse peritoneal macrophages. Biological and Pharmaceutical Bulletin, 30(5):912–916.


Faubel F, Lewis EC, Reznikov L et al. (2007). Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1 β , IL-18, IL-6, and neutrophil infiltration in the kidney. Journal of Pharmacology and Experimental Therapeutics, 322(1):8–15.


Ishiguro K, Ando T, Maeda O et al. (2006). Paeonol attenuates TNBS-induced colitis by inhibiting NF- κ B and STAT1 transactivation. Toxicology and Applied Pharmacology, 217(1):35–42.


Lee HJ, Lee GY, Kim Hs, Bae Hs. (2013). Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice. Evidence-Based Complementary and Alternative Medicine, 2013(2013), http://dx.doi.org/10.1155/2013/310989


Li N, Fan LL, Sun GP, et al. (2010). Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol., 16(35):4483-90.


Ramesh G, Reeves wb. (2002). TNF- α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. Journal of Clinical Investigation, 110(6):835–842.


Simmons EM, Himmelfarb j, Sezer MT et al. (2004). Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney International, 65(4):1357–1365.


Ye JM, Deng T, Zhang JB. (2009) Influence of paeonol on expression of COX-2 and p27 in HT-29 cells. World J Gastroenterol, 15(35):4410-4.

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

Oxymatrine (Ku Shen)

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

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

Anti-cancer

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

Angiogenesis

Oxymatrine has been found to inhibit angiogenesis when administered by injection. The tumor-inhibitory rate and the vascular density were tested in animal tumor model with experimental treatment. The expression of VEGF and bFGF were measured by immunistological methods. When high doses were used, the tumor-inhibitory rate of oxymatrine was 31.36%, and the vascular density of S180 sarcoma was lower than that in the control group, and the expression of VEGF and bFGF was down-regulated. Oxymatrine hence has an inhibitory effect on S180 sarcoma and strong inhibitory effects on angiogenesis. Its mechanism may be associated with the down-regulating of VEGF and bFGF expression (Kong et al., 2003).

Immunotolerance

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

The results showed that passage of the cells, and concentration and stimulation time of ionomycin on the cells, could influence the ability of T cell anergy induction. The cells exposed to matrine showed markedly decreased mRNA expression of interleukin-2, an indicator of T cell anergy, when the cells were stimulated by antigens, anti-OKT3 plus anti-CD28. Mechanistic study showed that ionomycin and matrine could up-regulate the anergy-associated gene expressions of CD98 and Jumonji and activate nuclear factor of activated T-cells (NFAT) nuclear translocation in absence of cooperation of AP-1 in Jurkat cells. Pre-incubation with matrine or ionomycin could also shorten extracellular signal-regulated kinase (ERK) and suppress c-Jun NH(2)-terminal kinase (JNK) expression on the anergic Jurkat cells when the cells were stimulated with anti-OKT-3 plus anti-CD28 antibodies. Thus, matrine is a strong candidate for further investigation as a T cell immunotolerance inducer (Li et al., 2010).

Induces Apoptosis

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

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

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

Pancreatic Cancer

Cell viability assay showed that treatment of PANC-1 pancreatic cancer cells with oxymatrine resulted in cell growth inhibition in a dose- and time-dependent manner. Oxymatrine decreased the expression of angiogenesis-associated factors, including nuclear factor κB (NF-κB) and vascular endothelial growth factor (VEGF). Finally, the anti-proliferative and anti-angiogenic effects of oxymatrine on human pancreatic cancer were further confirmed in pancreatic cancer xenograft tumors in nude mice (Chen et al., 2013).

Induces Apoptosis in Pancreatic Cancer

Oxymatrine inhibited cell viability and induced apoptosis of PANC-1 cells in a time- and dose-dependent manner. This was accompanied by down-regulated expression of Livin and Survivin genes while the Bax/Bcl-2 ratio was up-regulated. Furthermore, oxymatrine treatment led to the release of cytochrome c and activation of caspase-3 proteins. Oxymatrine can induce apoptotic cell death of human pancreatic cancer, which might be attributed to the regulation of Bcl-2 and IAP families, release of mitochondrial cytochrome c, and activation of caspase-3 (Ling et al., 2011).

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

The levels of sIL-2R and IL-8 in peripheral blood cells of patients with rectal cancer were measured after treatment with the compound matrine, in combination with radiation. Eighty-four patients diagnosed with rectal carcinoma were randomly divided into two groups: therapeutic group and control group.

The patients in the therapeutic group were treated with compound matrine and intensity- modulated radiation therapy (IMRT) (30 Gy/10 f/2 W), while the patients in control group were treated with IMRT. The clinical effects and the levels of IL-8 and sIL-2R tested by ELISA pre-radiation and post-radiation were compared. In addition, 42 healthy people were singled out from the physical examination center in the People's Hospital of Yichun city, which were considered as healthy controls.

The clinical effect and survival rate in the therapeutic group was significantly higher (47.6%) than those in the control group (21.4%). All patients were divided by improvement, stability, and progression of disease in accordance with Karnofsky Performance Scale (KPS). According to the KPS, 16 patients had improvement, 17 stabilized and 9 had disease progress, in the therapeutic group. However, the control group had 12 improvements, 14 stabilized, and 16 progress.

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

However, sIL-2R and IL-8 serum levels were found significantly lower in the 84 rectal cancer patients after radiotherapy. The level of sIL-2R and IL-8 in the therapeutic group was lower on the first and 14th day, post-radiation, when compared to the control group. However, there was no significant difference on the first day and 14th day, between both experimental groups post- therapy, according to the student test. Side-effects of hepatotoxicity (11.9%) and radiation proctitis (9.52%) were fewer in the therapeutic group.

Compound matrine can decrease the side-effects of IMRT, significantly inhibit sIL-2R and IL-8 in peripheral blood from radiation, and can improve survival quality in patients with rectal cancer (Yin et al., 2013).

Gastric Cancer

The clinical effect of matrine injection, combined with S-1 and cisplatin (SP), in the treatment of advanced gastric cancer was investigated. Seventy-six cases of advanced gastric cancer were randomly divided into either an experimental group or control group. Patients in the two groups were treated with matrine injection combined with SP regimen, or SP regimen alone, respectively.

The effectiveness rate of the experimental group and control group was 57.5% and 52.8% respectively. Therapeutic effect of the two groups of patients did not differ significantly. Occurrence rate of symptom indexes in the treatment group were lower than those of control group, with exception of nausea and vomiting, in which there was no significant difference.

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

Adenoid Cystic Carcinoma

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

Compound radix Sophorae flavescentis injection could inhibit the proliferation of ACC-2 cells in vitro, and the dosage effect relationship was significant (P < 0.01). IC50 of ACC-2 was 0.84 g/ml. Flow cytometry indicated that radix Sophorae flavescentis injection could arrest ACC-2 cells at the G0/G1 phase, with a gradual decrease of presence in the G2/M period and S phase. With an increase in dosage, ACC-2 cell apoptosis rate increased significantly (P < 0.05 or P < 0.01).

Radix Sophorae flavescentis injection could enhance ACC-2 cells Caspase-3 protein expression (P < 0.05 or P < 0.01), in a dose-dependent manner. It also could effectively restrain human adenoid cystic carcinoma ACC-2 cells Caspases-3 protein expression, and induce apoptosis, inhibiting tumor cell proliferation (Shi & Hu, 2012).

Breast Cancer Post-operative Chemotherapy

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

The objective remission rate of therapy group compared with that of control group was not statistically significant (P > 0.05), while the difference of the disease control rate in two groups was statistically significant (P < 0.05). The improvement rate of total quality of life in the therapy group was higher than that of the control group (P < 0.05). The drop of white blood cells and platelets, gastrointestinal reaction, elevated SGPT, and the incidence of hair loss in the therapy group were lower than those of the control group (P < 0.05).

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

Lung Cancer Pleural Effusions

The therapeutic efficiency of fufangkushen injection, IL-2, α-IFN on lung cancer accompanied with malignancy pleural effusions, was observed.

One hundred and fifty patients with lung cancer, accompanied with pleural effusions, were randomly divided into treatment and control groups. The treatment group was divided into three groups: injected fufangkushen plus IL-2, fufangkushen plus α-tFN, and IL-2 plus α-IFN, respectively. The control group was divided into three groups and injected fufangkushen, IL-2 and α-IFN, respectively. Therapeutic efficiency and adverse reactions were observed after four weeks.

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

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

Colorectal Cancer Immunologic Function

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

Eighty patients after colorectal cancer resection were randomly divided into two groups: 40 patients in the control group were treated with routine chemotherapy including 5-fluorouridine(5-FU), calcium folinate(CF) and oxaliplatin, and 40 patients in the experimental group were treated with the same chemotherapy regime combined with 20 mL·d-1 compound Kushen injection, for 10 days during chemotherapy.

In the control group the numbers of CD3+,CD4+T cells, NK cells and CD4+/CD8+ ratio significantly declined relative to prior to chemotherapy (P < 0.05), while CD8+T lymphocyte number increased significantly. In the experimental group, there were no significant differences between the numbers of CD3+,CD4+,CD8+T cells, NK cells, and CD4+/CD8+ ratio, before and after chemotherapy (P > 0.05).

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

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

A total of 286 patients with advanced NSCLC were enrolled for study. The patients were treated with either compound Kushen injection in combination with NP (NVB + CBP) chemotherapy (vinorelbine and carboplatin, n = 144), or with NP (NVB + CBP) chemotherapy alone (n = 142). The chemotherapy was performed for 4 cycles of 3 weeks, and the therapeutic efficacy was evaluated every 2 weeks. The following indicators were observed: levels of Hb, WBC, PLT and T cell subpopulations in blood, serum IgG level, short-term efficacy, adverse effects and quality of life.

The gastrointestinal reactions and the myelosuppression in the combination chemotherapy group were alleviated when compared with the chemotherapy alone group, showing a significant difference. (P < 0.05). CD (8)(+) cells were markedly declined in the combination chemotherapy group, and the CD (4)(+)/CD (8)(+) ratio showed an elevation trend in the chemotherapy alone group.

The Karnofsky Performance Scale (KPS) scores and serum IgM and IgG levels were higher in the combination chemotherapy group than those in the chemotherapy alone group (P < 0.01 and P < 0.05). The serum lgA levels were not significantly different in the two groups.

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

Lung Adenocarcinoma

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

Different concentrations of matrine injection could inhibit the growth of SPCA/I human lung adenocarcinoma cells. There was a positive correlation between the inhibition rate and the drug concentration. Different concentrations of matrine injection combined with anti-tumor drugs had a higher growth inhibition rate than anti-tumor drugs alone.

Matrine injection has direct growth suppression effect on SPCA/I human lung adenocarcinoma cells and SS+ injection combined with anti-tumor drugs shows a significant synergistic effect on tumor cells (Zhu, Jiang, Lu, Guo, & Gan, 2008).

Transcatheter Hepatic Arterial Chemoembolization (TACE)

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

Fifty-seven patients with unresectable primary liver cancer were randomly divided into two groups. The treatment group with 27 cases was treated by TACE combined with composite Kushen injection, and the control group with 30 cases was treated by TACE alone. The clinical curative effects were observed after treatment in both groups.

One-, 2-, and 3-year survival rates of the treatment group were 67%, 48%, and 37% respectively, and those of control group were 53%, 37%, and 20% respectively. There were significant differences between both groups (P < 0.05).

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

References

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


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


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


Fan CX, Lin CL, Liang L, et al. (2010). Enhancing effect of compound Kushen injection in combination with chemotherapy for patients with advanced non-small-cell lung cancer. Chinese Journal of Oncology, 32(4), 294-297.


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


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


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


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


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


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


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


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


Yin WH, Sheng JW, Xia HM, et al. (2013). Study on the effect of compound matrine on the level of sIL-2R and IL-8 in peripheral blood cells of patients with rectal cancer to radiation. Global Traditional Chinese Medicine, 2013(2), 100-104.


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


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

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

Oleanolic Acid (OA)

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

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

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

Pancreatic Cancer

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

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

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

Radio-sensitizer

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

Prostate Cancer, Lung Cancer, Gastric Cancer, Breast Cancer

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

Hepatocellular Carcinoma

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

References

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


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


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


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


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


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

A549, Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-tubulin, apoptosis, bFGF, Breast cancer, c-Jun, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, Cytostatic, cytotoxic, Dendrobrium loddigesii, ERK1, G1, G2/M, HCT-116, HIF, induces apoptosis, inflammation, iNOS, JNK, Lung cancer, MDA-MB-231, metastasis, Rectal cancer, ROS, Twist, VEGF, VEGF

Moscatilin

Cancers:
Colon, lung, placenta, stomach, breast metastasis

Action: Anti-angiogenic, anti-metastatic, anti-tubulin, cytostatic, cytotoxic, cell-cycle arrest, anti-inflammatory

Stomach Cancer, Lung Cancer, Placental

The efficacy of using moscatilin, a natural anti-platelet agent extracted from the stems of Dendrobrium loddigesii, as an anti-cancer agent was studied. Results demonstrated that moscatilin exerts potent cytotoxic effect against cancer cell lines derived from different tissue origins, including those from the placenta, stomach, and lung, but not those from the liver. In addition, the mechanism of action of moscatilin may be related to its ability to induce a G2 phase arrest in responsive cells.

However, unlike some G2 arresting agents, moscatilin has no detectable inhibitory effect on cyclin B–cdc-2 kinase activity. Thus, the precise nature of its cytotoxic mechanism remains to be determined.

Results suggest that moscatilin is potentially efficacious for chemo-prevention and/or chemotherapy against some types of cancer (Ho & Chen, 2003).

Colorectal Cancer

The growth inhibition of moscatilin was screened on several human cancer cell lines. The effect of moscatilin on tubulin was detected in vitro. Following moscatilin treatment on colorectal HCT-116 cells, c-Jun NH(2)-terminal protein kinase (JNK) and caspase activation was studied by Western blot analysis, and DNA damage was done by Comet assay. Moscatilin induced a time-dependent arrest of the cell-cycle at G2/M, with an increase of cells at sub-G1. Moscatilin inhibited tubulin polymerization, suggesting that it might bind to tubulins. A parallel experiment showed that SP600125 significantly inhibits Taxol and vincristine induced HCT-116 cell apoptosis. This suggests that the JNK activation may be a common mechanism for tubulin-binding agents.

Collectively, results suggest that moscatilin induces apoptosis of colorectal HCT-116 cells via tubulin depolymerization and DNA damage leading to the activation of JNK and mitochondria-involved intrinsic apoptosis pathway (Chen et al., 2008).

Anti-inflammatory

Results showed that moscatilin (10-100 microM) had a significant inhibition in a concentration-dependent manner on pro-inflammatory enzymes (COX-2 and iNOS) expression and macrophage activation under LPS (100 ng/mL) treatment.

Hypoxia-inducible factor 1 (HIF-1) alpha was reported to initiate inflammation under cytokine stimulation or hypoxic conditions. Moscatilin had significant inhibition on HIF-1 expression via down-regulation of HIF-1 mRNA without affecting cell viability, translation machinery, or proteasome-mediated degradation of HIF-1. Collective data demonstrarted that moscatilin inhibited both COX-2 and iNOS expressions after LPS treatment in RAW264.7. Furthermore, moscatilin's inhibitory effect appears to be dependent on the repression of HIF-1alpha accumulation and NF-kappaB activation (Liu et al., 2010).

Lung Cancer; Angiogenesis

Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs.

Results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy (Tsai et al., 2010).

Lung Cancer

Investigation demonstrated that non-toxic concentrations of moscatilin were able to inhibit human non-small-cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical was identified as a dominant species in the suppression of filopodia formation.

Results indicate a novel molecular basis of moscalitin inhibiting lung cancer cell motility and invasion. Moscalitin may have promising anti-metastatic potential as an agent for lung cancer therapy (Kowitdamrong, Chanvorachote, Sritularak & Pongrakhananon, 2013).

Breast Cancer; Metastasis

Moscatilin, derived from the orchid Dendrobrium loddigesii, has shown anti-cancer activity. The mechanism by which moscatilin suppresses the migration and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo was evaluated.

Moscatilin was found to significantly inhibit breast cancer MDA-MB-231 cell migration by using scratch assays and Boyden chambers.

In an MDA-MB-231 metastatic animal model, moscatilin (100 mg/kg) significantly suppressed breast cancer metastasis to the lungs and reduced the number of metastatic lung nodules and lung weight without causing any toxicity.

Results indicated that moscatilin inhibited MDA-MB-231 cell migration via Akt- and Twist-dependent pathways, consistent with moscatilin's anti-metastatic activity in vivo. Therefore, moscatilin may be an effective compound for the prevention of human breast cancer metastasis (Pai et al., 2013).

References

Chen TH, Pan SL, Guh JH, et al. (2008). Moscatilin induces apoptosis in human colorectal cancer cells: a crucial role of c-Jun NH2-terminal protein kinase activation caused by tubulin depolymerization and DNA damage. Clinical Cancer Research, 14(13), 4250-4258. doi: 10.1158/1078-0432.CCR-07-4578.


Ho CK, Chen CC. (2003). Moscatilin from the orchid Dendrobrium loddigesii is a potential anti-cancer agent. Cancer Investigation, 21(5), 729-736.


Kowitdamrong A, Chanvorachote P, Sritularak B, Pongrakhananon V. (2013). Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. BioMed Research International., 2013, 765894. doi: 10.1155/2013/765894.


Liu YN, Pan SL, Peng CY, et al. (2010). Moscatilin repressed lipopolysaccharide-induced HIF-1alpha accumulation and NF-kappaB activation in murine RAW264.7 cells. Shock, 33(1), 70-5. doi: 10.1097/SHK.0b013e3181a7ff4a.


Pai HC, Chang LH, Peng CY, et al. (2013). Moscatilin inhibits migration and metastasis of human breast cancer MDA-MB-231 cells through inhibition of Akt and Twist signaling pathway.

Journal of Molecular Medicine (Berlin), 91(3), 347-56. doi: 10.1007/s00109-012-0945-5.

Tsai AC, Pan SL, Liao CH, et al. (2010). Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo. Cancer Letters, 292(2), 163-70. doi: 10.1016/j.canlet.2009.11.020.

Akt, Akt/mTOR/P70S6K, AMPK, angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, apoptosis, Apoptotic, BAX, Bladder cancer, CD31, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, ERK, ERK1, FAK, G0/G1, G1, Glioblastoma, HCT-116, HER-2, HIF, IL-6, induces apoptosis, inhibits angiogenesis, JAK1, JAK2, Lung cancer, Magnolia officinalis, metastasis, MMP2, MTOR, Ovarian cancer, p21, p21/Cip1, p38, p53, P70S6K, PC3, PI3K, PI3K/Akt, PI3K/Akt/MTOR, Pro-apoptotic, Prostate cancer, STAT3, VEGF, VEGF

Magnolol

Cancer:
Bladder, breast, colon, prostate, glioblastoma, ovarian, leukemia, lung

Action: Anti-inflammatory, apoptosis, inhibits angiogenesis, anti-metastatic

Magnolol (Mag), an active constituent isolated from the Chinese herb hou po (Magnolia officinalis (Rehder & Wilson)) has long been used to suppress inflammatory processes. It has anti-cancer activity in colon, hepatoma, and leukemia cell lines.

Anti-inflammatory

Magnolol (Mag) suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. Pre-treatment of ECs with Mag dose-dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pre-treatment of these ECs dose-dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs).

In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis (Chen et al., 2006).

Bladder Cancer; Inhibits Angiogenesis

In the present study, Chen et al. (2013) demonstrated that magnolol significantly inhibited angiogenesis in vitro and in vivo, evidenced by the attenuation of hypoxia and vascular endothelial growth factor (VEGF)-induced tube formation of human umbilical vascular endothelial cells, vasculature generation in chicken chorioallantoic membrane, and Matrigel plug.

In hypoxic human bladder cancer cells (T24), treatment with magnolol inhibited hypoxia-stimulated H2O2 formation, HIF-1α induction including mRNA, protein expression, and transcriptional activity as well as VEGF secretion. Interestingly, magnolol also acts as a VEGFR2 antagonist, and subsequently attenuates the downstream AKT/mTOR/p70S6K/4E-BP-1 kinase activation both in hypoxic T24 cells and tumor tissues. As expected, administration of magnolol greatly attenuated tumor growth, angiogenesis and the protein expression of HIF-1α, VEGF, CD31, a marker of endothelial cells, and carbonic anhydrase IX, an endogenous marker for hypoxia, in the T24 xenograft mouse model.

Collectively, these findings strongly indicate that the anti-angiogenic activity of magnolol is, at least in part, mediated by suppressing HIF-1α/VEGF-dependent pathways, and suggest that magnolol may be a potential drug for human bladder cancer therapy.

Colon Cancer; Induces Apoptosis

Emerging evidence has suggested that activation of AMP-activated protein kinase (AMPK), a potential cancer therapeutic target, is involved in apoptosis in colon cancer cells. However, the effects of magnolol on human colon cancer through activation of AMPK remain unexplored.

Magnolol displayed several apoptotic features, including propidium iodide labeling, DNA fragmentation, and caspase-3 and poly(ADP-ribose) polymerase cleavages. Park et al. (2012) showed that magnolol induced the phosphorylation of AMPK in dose- and time-dependent manners.

Magnolol down-regulated expression of the anti-apoptotic protein Bcl2, up-regulated expression of pro-apoptotic protein p53 and Bax, and caused the release of mitochondrial cytochrome c. Magnolol-induced p53 and Bcl2 expression was abolished in the presence of compound C. Magnolol inhibited migration and invasion of HCT-116 cells through AMPK activation. These findings demonstrate that AMPK mediates the anti-cancer effects of magnolol through apoptosis in HCT-116 cells.

Ovarian Cancer

Treatment of HER-2 overexpressing ovarian cancer cells with magnolol down-regulated the HER-2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER-2 overexpressing ovarian cancer cells. These findings suggest that magnolol may act against HER-2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER-2mediated transformation and metastatic potential in HER-2 overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol (Chuang et al., 2011).

Lung Cancer

Magnolol has been found to inhibit cell growth, increase lactate dehydrogenase release, and modulate cell cycle in human lung carcinoma A549 cells. Magnolol induced the activation of caspase-3 and cleavage of Poly-(ADP)-ribose polymerase, and decreased the expression level of nuclear factor-κB/Rel A in the nucleus. In addition, magnolol inhibited basic fibroblast growth factor-induced proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that magnolol is a potential candidate for the treatment of human lung carcinoma (Seo et al., 2011).

Prostate Cancer; Anti-metastatic

Matrix metalloproteinases (MMPs) are enzymes involved in various steps of metastasis development. The objective of this study was to study the effects of magnolol on cancer invasion and metastasis using PC-3 human prostate carcinoma cells. Magnolol inhibited cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, magnolol showed 33 and 98% inhibition of cancer cell at 10 microM and 20 microM concentrations, respectively, compared to the control. The protein and mRNA levels of both MMP-2 and MMP-9 were down-regulated by magnolol treatment in a dose-dependent manner.

These results demonstrate the anti-metastatic properties of magnolol in inhibiting the adhesion, invasion, and migration of PC-3 human prostate cancer cells (Hwang et al., 2010).

Glioblastoma Cancer

Magnolol has been found to concentration-dependently (0-40 microM) decrease the cell number in a cultured human glioblastoma cancer cell line (U373) and arrest the cells at the G0/G1 phase of the cell-cycle.

Pre-treatment of U373 with p21/Cip1 specific antisense oligodeoxynucleotide prevented the magnolol-induced increase of p21/Cip1 protein levels and the decrease of DNA synthesis. Magnolol at a concentration of 100 microM induced DNA fragmentation in U373. These findings suggest the potential applications of magnolol in the treatment of human brain cancers (Chen et al. 2011).

Inhibits Angiogenesis

Magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF-induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs.

In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases (Kim et al., 2013).

References

Chen LC, Liu YC, Liang YC, Ho YS, Lee WS. (2009). Magnolol inhibits human glioblastoma cell proliferation through up-regulation of p21/Cip1. J Agric Food Chem, 57(16):7331-7. doi: 10.1021/jf901477g.


Chen MC, Lee CF, Huang WH, Chou TC. (2013). Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1 α /VEGF signaling pathway in human bladder cancer cells. Biochem Pharmacol, 85(9):1278-87. doi: 10.1016/j.bcp.2013.02.009.


Chen SC, Chang YL, Wang DL, Cheng JJ. (2006). Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells. Br J Pharmacol, 148(2): 226–232. doi: 10.1038/sj.bjp.0706647


Chuang TC, Hsu SC, Cheng YT, et al. (2011). Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells. Cancer Lett, 311(1):11-9. doi: 10.1016/j.canlet.2011.06.007.


Hwang ES, Park KK. (2010). Magnolol suppresses metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in PC-3 human prostate carcinoma cells. Biosci Biotechnol Biochem, 74(5):961-7.


Kim KM, Kim NS, Kim J, et al. (2013). Magnolol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Inhibiting Ras-Dependent Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways. Nutr Cancer.


Park JB, Lee MS, Cha EY, et al. (2012). Magnolol-induced apoptosis in HCT-116 colon cancer cells is associated with the AMP-activated protein kinase signaling pathway. Biol Pharm Bull, 35(9):1614-20.


Seo JU, Kim MH, Kim HM, Jeong HJ. (2011). Anti-cancer potential of magnolol for lung cancer treatment. Arch Pharm Res, 34(4):625-33. doi: 10.1007/s12272-011-0413-8.

apoptosis, Apoptotic, barley, BAX, Bcl-2, Breast cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Colon Cancer or Colorectal cancer, ERK, FAK, G1, G2/M, growth-inhibitory, Hordeum vulgare, IKK, including Glycine max, induces apoptosis, KM12L4, MDA-MB-23, MDR, metastasis, p21, p27, p65, Pro-apoptotic, S, Skin cancer, soy, wheat

Lunasin

Cancer: Colon, breast, liver metastasis

Action: Induces apoptosis, MDR

Lunasin is a peptide found in soy, barley, wheat, and rye, including Glycine max [(L.) Merr.], Hordeum vulgare L., Triticum (L.) genus and Secale cereale L.

Colon Cancer; Metastasis

Lunasin bound with α(5)β(1) integrin and internalized into the nucleus of KM12L4 human colon cancer cells. Lunasin (10µM) inhibited the activation of focal adhesion kinase (FAK) by 28%, 39% and 60% in RKO, HCT-116 and KM12L4 human colon cancer cells, respectively. Lunasin caused an increase in the expression of the inhibitor of kappa B alpha (IκB-α), a decrease in nuclear p50 NF-κB and a reduction in the migration of cancer cells. Lunasin (4mg/kg bw) inhibited metastasis and potentiated the effect of oxaliplatin by reducing the expression of proliferating cell nuclear antigen.

Liver metastatic nodules were reduced from 28 (PBS) to 14 (lunasin, P=0.047) while combination of lunasin and oxaliplatin to 5 (P=0.004). The tumor burden was reduced from 0.13 (PBS) to 0.10 (lunasin, P=0.039) to 0.04 (lunasin+oxaliplatin, P<0.0001). Moreover, lunasin potentiated the effect of oxaliplatin in modifying expression of proteins involved in apoptosis and metastasis including Bax, Bcl-2, IKK-α and p-p65. Lunasin inhibited metastasis of human colon cancer cells by direct binding with α(5)β(1) integrin suppressing FAK/ERK/NF-κB signaling, and potentiated the effect of oxaliplatin in preventing the outgrowth of metastasis (Dia et al., 2011).

Induces Apoptosis

Galvez et al. (2001) demonstrated previously that transfection of mammalian cells with the lunasin gene arrests mitosis, leading to cell death. Here they show that exogenous application of the lunasin peptide inhibits chemical carcinogen-induced transformation of murine fibroblast cells to cancerous foci. The results suggest a mechanism whereby lunasin selectively induces apoptosis, mostly in cells undergoing transformation, by preventing histone acetylation. In support of this, lunasin selectively induces apoptosis in E1A-transfected cells but not in nontransformed cells. Finally, in the SENCAR mouse skin cancer model, dermal application of lunasin (250 microg/week) reduces skin tumor incidence by approximately 70%, decreases tumor yield/mouse, and delays the appearance of tumors by 2 weeks relative to the positive control. These results point to the role of lunasin as a new chemo-preventive agent that functions possibly via a chromatin modification mechanism.

Breast Cancer

Combinations of two or more chemo-preventive agents are currently being used to achieve greater inhibitory effects on breast cancer cells. This study reveals that both aspirin and lunasin inhibit, in a dose-dependent manner, human estrogen-independent breast cancer MDA-MB-231 cell proliferation.

These compounds arrest the cell-cycle in the S- and G1-phases, respectively, acting synergistically to induce apoptosis. The cell growth-inhibitory effect of a lunasin/aspirin combination is achieved, at least partially, by modulating the expression of genes encoding G1 and S-phase regulatory proteins. Lunasin/aspirin therapy exerts its potent pro-apoptotic effect, at least partially achieved through modulating the extrinsic-apoptosis dependent pathway.

Therefore, our results suggest that a combination of these two compounds is a promising strategy to prevent/treat breast cancer (Hsieh et al., 2010).

Colon Cancer; MDR

Various human colon cancer cell lines which underwent metastasis were evaluated in vitro using cell flow cytometry and fluorescence microscopy. Lunasin cytotoxicity to different colon cancer cells correlated with the expression of α5b1 integrin was investigated, being most potent to KM12L4 cells (IC50 = 13 µM). Lunasin arrested cell-cycle at G2/M phase with concomitant increase in the expression of cyclin-dependent kinase inhibitors p21 and p27. Lunasin (5–25 µM) activated the apoptotic mitochondrial pathway as evidenced by changes in the expressions of Bcl-2, Bax, nuclear clusterin, cytochrome c and caspase-3 in KM12L4 and KM12L4-OxR.

Lunasin increased the activity of initiator caspase-9 leading to the activation of caspase-3 and also modified the expression of human extracellular matrix and adhesion genes, down-regulating integrin α5, SELE, MMP10, integrin β2 and COL6A1 by 5.01-, 6.53-, 7.71-, 8.19- and 10.10-fold, respectively, while up-regulating COL12A1 by 11.61-fold. Lunasin can be used in cases where resistance to chemotherapy developed (Dia et al., 2011).

References

Dia VP, Gonzalez de Mejia E. (2011). Lunasin potentiates the effect of oxaliplatin preventing outgrowth of colon cancer metastasis, binds to α5β1 integrin and suppresses FAK/ERK/NF-κ B signaling, Cancer Lett, 313(2):167-80.


Dia VP, Gonzalez de Mejia E. (2011). Lunasin induces apoptosis and modifies the expression of genes associated with extracellular matrix and cell adhesion in human metastatic colon cancer cells. Mol Nutr Food Res, 55(4):623-34. doi: 10.1002/mnfr.201000419.


Galvez AF, Chen N, Macasieb J, de Lumen BO. (2001). Chemo-preventive property of a soybean peptide (lunasin) that binds to deacetylated histones and inhibits acetylation. Cancer Res, 61(20):7473-8.


Hsieh CC, Hern‡ndez-Ledesma B, de Lumen BO. (2010). Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell-cycle and induced apoptosis. Chem Biol Interact, 186(2):127-34. doi: 10.1016/j.cbi.2010.04.027.

anti-tumor, anti-tumor activity, apoptosis, Cephalotaxus harringtonia, Chapter 7 Isolates and Cancer Research, cytotoxic, induces apoptosis

Homoharringtonine/Omacetaxine

Cancer:
Leukemia, AML, CML, myelodysplastic syndrome (MDS)

Action: Induces apoptosis, anti-tumor activity

Homoharringtonine (also known as Omacetaxine mepesuccinate) is isolated from Cephalotaxus harringtonia (K.Koch).

Homoharringtonine/omacetaxine is a unique agent with a long history of research development. It has been recently approved by the Food and Drug Administration for the treatment of chronic myeloid leukemia after failure of 2 or more tyrosine kinase inhibitors. Research with this agent has spanned over 40 years (Kantarjian, O'Brien, & Cortes, 2013).

Leukemia

Homoharringtonine (HHT), first isolated from the Chinese evergreen Cephalotaxus harringtonia, has been demonstrated to have a broad anti-tumor activity in rodents and anti-leukemic effects in humans. It was found that HHT was metabolized to an acid product [HHT acid; 2'hydroxy2' (acetic acid) 6'hydroxy6'methylheptanoyl cephalotaxine] when incubated with either human plasma or mouse plasma in vitro. The HHT concentration inhibiting 50% of the growth of human leukemic HL60 cells was 20 ng/ml, while for HHT acid it was 14,500 ng/ml, indicating that the acid form was more than 700 times less cytotoxic than HHT. The lethal dose of HHT affecting 50%(LD50) of mice was 6.7 mg/kg, but HHT acid produced no apparent toxic effects at doses up to 280 mg/kg (Ni et al., 2003).

Acute Myeloid Leukemia (AML)

The response to remission induction in elderly patients with acute myeloid leukemia (AML) remains poor. Patients were treated with the HA regimen consisting of homoharringtonine (2 mg/m2/day for 7 days) and cytarabine (Ara-C, 100 mg/m2/day for 7 days). The overall response rate was 56.5% with complete remission (CR) rate of 39.1% and partial remission of 17.4%.

There was no early death in this cohort of patients. The estimated median overall survival (OS) time of all patients was (12.0 ± 3.0) months. The estimated OS time of the CR patients was 15 months. The estimated one-year OS rate of all patients treated with HA protocol was (49.3 ± 13.5) %. The estimated one-year OS rate of the CR patients was (62.5 ± 17.1) % (Wang et al., 2009).

Leukemia; Telomerase

The effect of HHT on the telomerase activity and apoptosis of human leukemia HL-60 cells was investigated. Telomerase activity of HL-60 cells was examined by the telomeric repeat amplification protocol (TRAP)–an enzyme-linked immunosorbent assay (ELISA). Apoptosis was analyzed by morphological observation, DNA agarose gel electrophoresis, flow cytometry (FCM), and TdT-mediated dUTP-biotin nick end labeling (TUNEL).

After treatment with HHT at 5-500 microg/l for 48 hours, the level of telomerase activity in HL-60 cells decreased in a dose-and time-dependent manner. Simultaneously, HL-60 cells underwent apoptosis. In conclusion, these data suggest that HHT can inhibit the telomerase content of HL- 60 cells effectively and induce apoptosis (Xie et al., 2006).

Chronic Myeloid Leukemia (CML)

Evidence confirmed HHT as an apoptosis inducer in tumor cell lines and fresh cells from cancer patients. The CR rate reported with HHT-based regimen in acute nonlymphocytic leukemia showed no statistical differences from that with DNR-based regimen, although the case number was limited.

Although with anti-growth activity in vitro and laudable achievement in acute and chronic myeloid leukemia treatment, the drug shows no beneficial effect in lymphocytic leukemia and solid tumors. The underlying mechanism for the discrepancy of efficacy remains unknown, and is a subject for further research (Luo et al., 2004).

Myelodysplastic Syndrome (MDS)

Homoharringtonine might have clinical activity in some patients with myelodysplastic syndrome (MDS) (Daver et al., 2013).

References

Daver N, Vega-Ruiz A, Kantarjian HM, et al. (2013). A phase II open-label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome. Eur J Cancer Care, 22(5):605-11. doi: 10.1111/ecc.12065.


Kantarjian HM, O'Brien S, Cortes J. (2013). Homoharringtonine/Omacetaxine mepesuccinate: the long and winding road to food and drug administration approval. Clin Lymphoma Myeloma Leuk, 13(5):530-3. doi: 10.1016/j.clml.2013.03.017.


Luo CY, Tang JY, Wang YP. (2004). Homoharringtonine: a new treatment option for myeloid leukemia. Hematology, 9(4):259-70.


Ni D, Ho DH, Vijjeswarapu M, et al. (2003). Metabolism of homoharringtonine, a cytotoxic component of the evergreen plant Cephalotaxus harringtonia. Journal of Experimental Therapeutics and Oncology, 3(1):47.


Wang J, LŸ S, Yang J, et al. (2009). A homoharringtonine-based induction regimen for the treatment of elderly patients with acute myeloid leukemia: a single center experience from China. Journal of Hematology & Oncology, 2:32. doi:10.1186/1756-8722-2-32


Xie WZ, Lin MF, Huang H, Cai Z. (2006). Homoharringtonine-induced apoptosis of human leukemia HL-60 cells is associated with down-regulation of telomerase. Am J Chin Med, 34(2):233-44.

anti-tumor, apoptosis, apoptosis-inducing, Breast cancer, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, GADD153, induces apoptosis, Prostate cancer, Prostate cancer cell lines

Glycyrrhiza Uralensis: Glycyrrhizin, Isoliquiritigenin

Cancer:
Cervical., breast, stomach, liver, hepatoma, prostate

Action: Induces apoptosis

The active components of Glycyrrhiza uralensis include the total flavones extracted from Chinese licorice, Glycyrrhiza uralensis Fisch.

Stomach Cancer, Hepatoma, Breast Cancer, Cervical Cancer

The anti-proliferation effect of glycyrrhizhin and total flavones extracted from Chinese licorice, Glycyrrhiza uralensis Fisch, on four kinds of human cancer cells (cervix tumor cell; Hela, breast tumor cell; Bcap-37, stomach tumor cell; MGC-803 and hepatoma cell; Bel-7404) were studied. MTT showed that the anti-proliferation effect of glycyrrhizin was concentration-dependent; higher concentration of glycyrrhizin (1000µg/ml) had obvious anti-tumor effect; within certain concentrations of (200~1000µg/ml), inhibitory effect of total flavones was also concentration dependent; the lower concentration (200µg/ml) was of the highest inhibitory effect: its inhibiting rates on Bcap-37, Hela, Bel-7404, MGC-803 were 79.55%, 79.98%, 67.91% and 37.86% respectively.

Both glycyrrhizin and total flavones have stronger apoptosis-inducing effects on the four kinds of tumor cells (Ma et al., 2008).

Prostate Cancer

Kanazawa et al. (2003) investigated the anti-tumor effect of isoliquiritigenin on prostate cancer in vitro. DU145 and LNCaP prostate cancer cell lines were used as targets. The effects of isoliquiritigenin were examined on cell proliferation, cell-cycle regulation and cell-cycle-regulating gene expression. Further, they investigated the effects of isoliquiritigenin on the GADD153 mRNA and protein expression, and promoter activity. Isoliquiritigenin significantly inhibited the proliferation of prostate cancer cell lines in a dose-dependent and time-dependent manner. These findings suggest that isoliquiritigenin is a candidate agent for the treatment of prostate cancer and GADD153 may play an important role in isoliquiritigenin-induced cell-cycle arrest and cell growth inhibition.

References

Kanazawa M, Satomi Y, Mizutani Y, et al. (2003). Isoliquiritigenin inhibits the growth of prostate cancer. Eur Urol. 43(5):580-6.


Ma M, Zhou X-l, Hu Y-l, et al. (2008). Lishizhen Medicine and Materia Medica Research. doi: CNKI:SUN:SZGY.0.2008-01-006