Category Archives: Cytostatic

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

 

 

 

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

Periplocin

Cancer: Lung, colorectal, leukemia

Action: Apoptosis-inducing, cytostatic effect

Apoptosis

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

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

Lung Cancer

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

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

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

Colorectal Carcinomas

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

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

Pro-apoptotic and Cytostatic Effect/Leukemia

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

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

References

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


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


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


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

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

Oxymatrine (Ku Shen)

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

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

Anti-cancer

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

Angiogenesis

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

Immunotolerance

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

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

Induces Apoptosis

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

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

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

Pancreatic Cancer

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

Induces Apoptosis in Pancreatic Cancer

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

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

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

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

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

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

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

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

Gastric Cancer

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

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

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

Adenoid Cystic Carcinoma

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

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

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

Breast Cancer Post-operative Chemotherapy

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

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

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

Lung Cancer Pleural Effusions

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

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

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

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

Colorectal Cancer Immunologic Function

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

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

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

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

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

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

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

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

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

Lung Adenocarcinoma

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

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

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

Transcatheter Hepatic Arterial Chemoembolization (TACE)

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

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

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

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

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

Nelumbo Extract (NLE):Neferine

Cancer: Liver, osteosarcoma, breast, melanoma

Action: Anti-angiogenic, cytostatic

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

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

Hepatitis

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

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

Osteosarcoma

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

Breast Cancer

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

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

Melanoma

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

References

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


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


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


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

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.

Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Bladder cancer, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Cytostatic, cytotoxic, Down-regulates, ERK, ERK1, Hep3B, JNK, Liver cancer, MAPK, p21, p38, p53, PARP, Phellinus igniarius, pro-oxidative, ROS, S

Hispolon

Cancer: Bladder, breast, liver, gastric

Action: Anti-inflammatory, cytostatic, cytotoxic, pro-oxidative, anti-proliferative

Hispolon is an active phenolic compound of Phellinus igniarius , a mushroom that has recently been shown to have anti-oxidant, anti-inflammatory, and anti-cancer activities.

Liver Cancer

Hispolon inhibited cellular growth of Hep3B cells in a time-dependent and dose-dependent manner, through the induction of cell-cycle arrest at S phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Exposure of Hep3B cells to hispolon resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. Hispolon treatment also activated JNK, p38 MAPK, and ERK expression. Inhibitors of ERK (PB98095), but not those of JNK (SP600125) and p38 MAPK (SB203580), suppressed hispolon-induced S-phase arrest and apoptosis in Hep3B cells.

These findings establish a mechanistic link between the MAPK pathway and hispolon-induced cell-cycle arrest and apoptosis in Hep3B cells (Huang et al., 2011).

Gastric Cancer, Breast Cancer, Bladder Cancer

Hispolon extracted from Phellinus species was found to induce epidermoid and gastric cancer cell apoptosis. Hispolon has also been found to inhibit breast and bladder cancer cell growth, regardless of p53 status. Furthermore, p21(WAF1), a cyclin-dependent kinase inhibitor, was elevated in hispolon-treated cells. MDM2, a negative regulator of p21(WAF1), was ubiquitinated and degraded after hispolon treatment.

Lu et al. (2009) also found that activated ERK1/2 (extracellular signal-regulated kinase1/2) was recruited to MDM2 and involved in mediating MDM2 ubiquitination. The results indicated that cells with higher ERK1/2 activity were more sensitive to hispolon. In addition, hispolon-induced caspase-7 cleavage was inhibited by the ERK1/2 inhibitor, U0126.

In conclusion, hispolon ubiquitinates and down-regulates MDM2 via MDM2-recruited activated ERK1/2. Therefore, hispolon may be a potential anti-tumor agent in breast and bladder cancers.

Gastric Cancer

The efficacy of hispolon in human gastric cancer cells and cell death mechanism was explored. Hispolon induced ROS-mediated apoptosis in gastric cancer cells and was more toxic toward gastric cancer cells than toward normal gastric cells, suggesting greater susceptibility of the malignant cells.

The mechanism of hispolon-induced apoptosis was that hispolon abrogated the glutathione anti-oxidant system and caused massive ROS accumulation in gastric cancer cells. Excessive ROS caused oxidative damage to the mitochondrial membranes and impaired the membrane integrity, leading to cytochrome c release, caspase activation, and apoptosis. Furthermore, hispolon potentiated the cytotoxicity of chemotherapeutic agents used in the clinical management of gastric cancer.

These results suggest that hispolon could be useful for the treatment of gastric cancer either as a single agent or in combination with other anti-cancer agents (Chen et al., 2008).

Anti-proliferative Activity

Hispolon, which lacks one aromatic unit in relation to curcumin, exhibits enhanced anti-inflammatory and anti-proliferative activities. Dehydroxy hispolon was least potent for all three activities. Overall the results indicate that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7(th) position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin and hispolon (Ravindran et al., 2010).

References

Chen W, Zhao Z, Li L, et al. (2008). Hispolon induces apoptosis in human gastric cancer cells through a ROS-mediated mitochondrial pathway. Free Radic Biol Med, 45(1):60-72. doi: 10.1016/j.freeradbiomed.2008.03.013.


Huang GJ, Deng JS, Huang SS, Hu ML. (2011). Hispolon induces apoptosis and cell-cycle arrest of human hepatocellular carcinoma Hep3B cells by modulating ERK phosphorylation. J Agric Food Chem, 59(13):7104-13. doi: 10.1021/jf201289e.


Lu TL, Huang GJ, Lu TJ, et al. (2009). Hispolon from Phellinus linteus has anti-proliferative effects via MDM2-recruited ERK1/2 activity in breast and bladder cancer cells. Food Chem Toxicol, 47(8):2013-21. doi: 10.1016/j.fct.2009.05.023.


Ravindran J, Subbaraju GV, Ramani MV, et al. (2010). Bisdemethylcurcumin and structurally related hispolon analogues of curcumin exhibit enhanced prooxidant, anti-proliferative and anti-inflammatory activities in vitro. Biochem Pharmacol, 79(11):1658-66. doi: 10.1016/j.bcp.2010.01.033.

anti-proliferative, anti-tumor, apoptosis, Apoptotic, BAX, c-Fos, c-Jun, CDK4, Cervical cancer, Chapter 7 Isolates and Cancer Research, Chemoprevention, Cytostatic, ERK1, FasL, G1, Hep3B, hepato-protective, induces apoptosis, JNK, Melanoma, Neuroblastoma, p21, p53, PI3K, PKC, Prostate cancer

Geniposide –Penta-acetyl Geniposide (Ac)5GP

Cancers:
Glioma, melanoma, liver, hepatocarcinogenesis, hepatoma, prostate, cervical

Action: Cytostatic, induces apoptosis

Gardenia, the fruit of Gardenia jasminoides Ellis, has been widely used to treat liver and gall bladder disorders in Chinese medicine. It has been shown recently that geniposide, the main ingredient of Gardenia fructus , exhibits anti-tumor effect.

Hepatocarcinogenesis, Glioma

It has been demonstrated that (Ac)5GP plays more potent roles than geniposide in chemoprevention. (Ac)5GP decreased DNA damage and hepatocarcinogenesis, induced by aflatoxin B1 (AFB1), by activating the phase II enzymes glutathione S-transferase (GST) and GSH peroxidase (GSH-Px). It reduced the growth and development of inoculated C6 glioma cells, especially in pre-treated rats. In addition to the preventive effect, (Ac)5GP exerts its actions on apoptosis and growth arrest.

Treatment of (Ac)5GP caused DNA fragmentation of glioma cells. (Ac)5GP induced sub- G1 peak through the activation of apoptotic cascades PKCdelta/JNK/Fas/caspase8 and caspase 3. It arrested the cell-cycle at G0/ G1 by inducing the expression of p21, thus suppressing the cyclin D1/cdk4 complex formation and the phosphorylation of E2F.

Data from in vivo experiments indicated that (Ac)5GP is not harmful to the liver, heart and kidney. (Ac)5GP is strongly suggested to be an anti-tumor agent for development in the future (Peng, Huang, & Wang, 2005).

Induces Apoptosis

Previous studies have demonstrated the apoptotic cascades protein kinase C (PKC) delta/c-Jun NH2-terminal kinase (JNK)/Fas/caspases induced by penta-acetyl geniposide [(Ac)5GP]. However, the upstream signals mediating PKCdelta activation have not yet been clarified. Ceramide, mainly generated from the degradation of sphingomyelin, was hypothesized upstream above PKCdelta in (Ac)5GP-transduced apoptosis.

After investigation, (Ac)5GP was shown to activate neutral sphingomyelinase (N-SMase) immediately, with its maximum at 15 min. The NGF and p75 enhanced by (Ac)5GP was inhibited when combined with GW4869, the N-SMase inhibitor, indicating NGF/p75 as the downstream signals of N-SMase/ceramide. To evaluate whether N-SMase is involved in (Ac)5GP-transduced apoptotic pathway, cells were treated with (Ac)5GP, alone or combined with GW4869. It was demonstrated that N-SMase inhibition blocked FasL expression and caspase 3 activation. Similarly, p75 antagonist peptide attenuated the FasL/caspase 3 expression. It indicated that N-SMase activation is pivotal in (Ac)5GP-mediated apoptosis.

SMase and NGF/p75 are suggested to mediate upstream above PKCdelta, thus transducing FasL/caspase cascades in (Ac)5GP-induced apoptosis (Peng, Huang, Hsu, & Wang, 2006).

Glioma

Penta-acetyl geniposide [(Ac)(5)GP], an acetylated geniposide product from Gardenia fructus, has been known to have hepato-protective properties and recent studies have revealed its anti-proliferative and apoptotic effect on C6 glioma cells. The anti-metastastic effect of (Ac)(5)GP in the rat neuroblastoma line C6 glioma cells were investigated.

Further (Ac)(5)GP also exerted an inhibitory effect on phosphoinositide 3-kinase (PI3K) protein expression, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inhibition of activation of transcription factor nuclear factor kappa B (NF-kappaB), c-Fos, c-Jun.

Findings suggest (Ac)(5)GP is highly likely to be an inhibiting cancer migration agent to be further developed in the future (Huang et al., 2009).

Melanoma

A new iridoid glycoside, 10-O-(4'-O-methylsuccinoyl) geniposide, and two new pyronane glycosides, jasminosides Q and R, along with nine known iridoid glycosides, and two known pyronane glycosides, were isolated from a MeOH extract of Gardeniae Fructus, the dried ripe fruit of Gardenia jasminoides (Rubiaceae).

The structures of new compounds were elucidated on the basis of extensive spectroscopic analyzes and comparison with literature. Upon evaluation of these compounds on the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, i.e., 6-O-p-coumaroylgeniposide (3), 7, and 6'-O-sinapoyljasminoside (12), exhibited inhibitory effects with 21.6-41.0 and 37.5-47.7% reduction of melanin content at 30 and 50 µM, respectively, with almost no toxicity to the cells (83.7-106.1% of cell viability at 50 µM) (Akisha et al., 2012).

Hepatoma, Prostate Cancer, Cervical Cancer

Genipin is a metabolite of geniposide isolated from an extract of Gardenia fructus. Some observations suggested that genipin could induce cell apoptosis in hepatoma cells and PC3 human prostate cancer cells. Genipin could remarkably induce cytotoxicity in HeLa cells and inhibit its proliferation. Induction of the apoptosis by genipin was confirmed by analysis of DNA fragmentation and induction of sub-G(1) peak through flow cytometry.

The results also showed that genipin-treated HeLa cells cycle was arrested at G(1) phase. Western blot analysis revealed that the phosphorylated c-Jun NH(2)-terminal kinase (JNK) protein, phospho-Jun protein, p53 protein and bax protein significantly increased in a dose-dependent manner after treatment of genipin for 24 hours; the activation of JNK may result in the increase of the p53 protein level; the increase of the p53 protein led to the accumulation of bax protein; and bax protein further induced cell apoptotic death eventually (Cao et al., 2010).

References

Akihisa T, Watanabe K, Yamamoto A, et al. (2012). Melanogenesis inhibitory activity of monoterpene glycosides from Gardeniae Fructus. Chemistry & Biodiversity, 9(8), 1490-9. doi: 10.1002/cbdv.201200030.


Cao H, Feng Q, Xu W, et al. (2010). Genipin induced apoptosis associated with activation of the c-Jun NH2-terminal kinase and p53 protein in HeLa cells. Biol Pharm Bull, 33(8):1343-8.


Huang HP, Shih YW, Wu CH, et al. (2009). Inhibitory effect of penta-acetyl geniposide on C6 glioma cells metastasis by inhibiting matrix metalloproteinase-2 expression involved in both the PI3K and ERK signaling pathways. Chemico-biological Interactions, 181(1), 8-14. doi: 10.1016/j.cbi.2009.05.009.


Peng CH, Huang CN, Hsu SP, Wang CJ. (2006). Penta-acetyl geniposide induce apoptosis in C6 glioma cells by modulating the activation of neutral sphingomyelinase-induced p75 nerve growth factor receptor and protein kinase Cdelta pathway. Molecular Pharmacology, 70(3), 997-1004.


Peng CH, Huang CN, Wang CJ. (2005). The anti-tumor effect and mechanisms of action of penta-acetyl geniposide. Current Cancer Drug Targets, 5(4), 299-305.

ABC, Anti-cancer, Anti-metastatic, apoptosis, apoptosis induction, Breast cancer, CDK2, Chapter 7 Isolates and Cancer Research, Cytostatic, G1, G2/M, KIP1, lymphangiogenesis inhibitors, Nausea and Vomiting, p27, PARP, Prostate cancer, S, Sarcoma, TIMP-2

Dehydrocostus (See also costunolide)

Cancers: Breast, cervical., lung, prostate, sarcoma

Action: Anti-metastatic, cytostatic, lymphangiogenesis inhibitors

Saussurea lappa has been used in Chinese traditional medicine for the treatment of abdominal pain, tenesmus, nausea, and cancer. Previous studies have shown that S. lappa also induces G2 growth arrest and apoptosis in gastric cancer cells.

Prostate Cancer

The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated. DU145 and TRAMP-C2 cells were cultured in the presence of 0-4 µg/mL HESL with or without 10 ng/mL epidermal growth factor (EGF).

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

Results demonstrated that the inhibition of MMP-9 secretion, and the stimulation of TIMP-2 secretion, contribute to reduced migration of DU145 cells treated with HESL and DHCL. This indicates that HESL containing its active principle, DHCL, has potential as an anti-metastatic agent in the treatment of prostate cancer (Kim et al., 2012).

Sarcoma

Human soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment. The effects of the costunolide and dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, were studied on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. Both compounds inhibited cell viability dose- and time-dependently.

IC50 values ranged from 6.2 µg/mL to 9.8 µg/mL. Cells treated with costunolide showed no changes in cell-cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 hours. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase.

These data demonstrate for the first time that dehydrocostus lactone affects cell viability, cell-cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumors (Kretschmer et al., 2012).

The effects of the sesquiterpene lactones, costunolide and dehydrocostus, on the cell-cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner.

Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27 (Kip1).

In the presence of costunolide, MMP-2 and MMP-9 levels were significantly increased in SW-982 and TE-671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and MMP-9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlock insert system (Lohberger et al., 2013).

Breast Cancer

Several Chinese herbs, namely, pu gong ying (Taraxacum officinale), gan cao (Glycyrrhizae uralensis), chai hu (Bupleurum chinense), mu xiang (Auklandia lappa), gua lou (Trichosanthes kirilowii) and huang yao zi (Dioscoreae bulbiferae), are frequently used in complex traditional Chinese medicine formulas, for breast hyperplasia and breast tumor therapy. The effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. However, the chemical profiles of anti-breast cancer constituents in these herbs have not been investigated thus far.

Two potential anti-breast cancer compounds, costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in mu xiang. The combination of the two compounds showed a synergistic effect on inhibiting the proliferation of MCF-7 cells in vitro, exhibiting potential application in the treatment of breast cancer (Peng, Wang, Gu, Wen & Yan, 2013).

Lymphangiogenesis Inhibitors

In this study, we investigated lymphangiogenesis inhibitors from crude drugs used in Japan and Korea. The three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro. These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong, 2013).

References

Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biological & Pharmaceutical Bulletin, 36(1), 152-7.


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


Kretschmer N, Rinner B, Stuendl N, et al. (2012). Effect of costunolide and dehydrocostus lactone on cell-cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Planta Medica, 78(16), 1749-1756. doi: 10.1055/s-0032-1315385.


Lohberger B, Rinner B, Stuendl N, et al. (2013). Sesquiterpene lactones downregulate g2/m cell-cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells. PLoS One, 8(6), e66300. doi: 10.1371/journal.pone.0066300.


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

anti-tumor, apoptosis, Bufo gargarizans, CDK2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, chemotherapy support, Cytostatic, inhibits proliferation, Liver cancer, Lung cancer, metastasis, S, VEGFR

Cinobufacini

Cancers: Liver, lung

Action: Chemo-sensitizer, chemotherapy support, cytostatic

Hepatic Cancer

Cinobufacini injection significantly inhibits proliferation, heterogeneous adhesion and invasiveness of hepG-2 cells co-cultured with HLEC in dose-dependent ways (all P0.05). Cinobufacini injection can inhibit the capability of proliferation, invasiveness and heterogeneous adhesion of HepG-2 cells, which might contribute to the inhibiting mechanisms of Cinobufacini injection on tumor metastasis (Fu, Gao, Tian, Chen, & Cui, 2013).

Human Lymphatic Endothelial Cells

Cinobufacini injection is a traditional anti-tumor drug. However, its mechanism of action is still unclear. The effects of Cinobufacini injection on proliferation, migration and tubulin formation of human lymphatic endothelial cells (HLEC) was investigated.

Cell growth curve was used to observe the effect of Cinobufacini injection on the proliferation of HLEC; migration assay was used to observe the effect of Cinobufacini injection on the migration of HLEC; Matrigel assay was used to observe the effect of Cinobufacini injection on the tubulin formation of HLEC; Western blot was used to analyze the expression of VEGFR-3 and HGF in HLEC.

Cinobufacini injection significantly inhibits HLEC proliferation, migration, and tubulin formation. The down-regulation of VEGFR-3 and HGF may contribute to the inhibitory effect of Cinobufacini injection on HLEC (Gao, Chen, Xiu, Fu, & Cui, 2013).

NSCLC

The efficacy and safety of Cinobufacini injection, combined with chemotherapy, as a treatment for advanced non-small-cell lung cancer (NSCLC) was investigated. Based on existing clinical information, a search of databases, such as MEDLINEe (1966-2011), Cochrane Library (2011, Issue 11), CNKI (1978-2011), VIP (1989-2011), Wanfang Data (1988-2011), CBMdisc (1978-2011) was done.

Cinobufacini, combined with chemotherapy, is suitable for advanced NSCLC by improving the response rate, increasing Karnofsky score, gaining weight and reducing major side-effects (Tu, Yin, & He, 2012).

Liver Cancer

Seventy-eight patients with moderate and advanced primary liver cancer were randomly divided. The treatment group (n=38) was treated by Cinobufacini injection combined with transcatheter arterial chemoembolization (TACE), and the control group (n=40), was treated by TACE only.

Quality of life of patients in the treatment group was significantly higher than that in control group. The 12 months survival rate of the treatment group was significantly higher than that of the control group. Cinobufacini injection, combined with TACE, can decrease TACE-induced liver damage, prolong survival time, and improve body immunity (Ke, Lu, & Li, 2011).

Cinobufacini injection significantly inhibited HepG-2 cells proliferation in a dose- and time- dependent manner. FCM analysis showed Cinobufacini injection induced cell-cycle arrest at the S phase. RT-PCR assay showed Cinobufacini injection down-regulated Cyclin A, and CDK2 expression at mRNA levels. Quantitative colorimetric assay showed Cinobufacini injection deceased Cyclin A/CDK2 activity in HepG-2 cells.

Cinobufacini injection can inhibit human hepatoma HepG-2 cells growth, induce cell apoptosis and induce cell-cycle arrest at the S phase. Its mechanism might be partly related to the down-regulation of Cyclin A, CDK2 mRNA expression, and inhibition of Cyclin A/CDK2 activity (Sun, Lu, Liang, & Cui, 2011).

References

Fu HY, Gao S, Tian LL, Chen XY, Cui XN. (2013). Effect of Cinobufacini injection on proliferation and invasiveness of human hepatoma HepG-2 cells co-cultured with human lymphatic endothelial cells. The Chinese Journal of Clinical Pharmacology, 29(3), 199-201.


Gao S, Chen XY, Fu HY, Cui XZ. (2013). The effect of Cinobufacini injection on proliferation and tube-like structure formation of human lymphatic endothelial cells. China Oncology, 23(1), 36-41.


Ke J, Lu K, Li Y. (2011). Clinical observation of patients with primary liver cancer treated by Cinobufagin Injection combined with transcatheter arterial chemoembolization. Chinese Journal of Clinical Hepatology,


Sun Y, Lu XX, Liang XM, Cui XN. (2011). Impact of Cinobufacini injection on proliferation and cell-cycle of human hepatoma HepG-2 cells. The Chinese-German Journal of Clinical Oncology, 10(6), 321-324.


Tu C, Yin J, He J. (2012). Meta-analysis of Cinobufacini injection plus chemotherapy in the treatment of non-small-cell lung cancer. Anti-tumor Pharmacy, 2(1), 67-72.

Anti-cancer, apoptosis, Apoptotic, Breast cancer, Breast cancer cell lines, Camptotheca acuminata, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, Cytostatic, MCF-7, MDA-MB-468, p53

Camptothecin

Cancer: Breast, colon

Action: Cytostatic

Breast Cancer

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

The elevation of p53 protein levels in MCF-7 cells treated with CPT was significantly inhibited by preincubation with DNA breaks inhibitor aphidicolin, while the elevation of p21WAF1/CIP1 protein levels was not inhibited. The elevation of p21WAF1/CIP1 in MDA-MB-468 cells treated with CPT was not inhibited by aphidicolin. Using Northern blot analysis, the transcription of p21WAF1/CIP1 was shown to increase in a dose-dependent manner in MCF-7 and MDA-MB-468 cells treated with HCPT or CPT.

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

Colon Cancer

10-Hydroxycamptothecin (10-HCPT), an indole alkaloid isolated from a Chinese tree, Camptotheca acuminate , inhibits the activity of topoisomerase I and has a broad spectrum of anti-cancer activity in vitro and in vivo. 10-HCPT significantly repressed the proliferation of Colo 205 cells at a relatively low concentration (5-20 nM). Flow cytometry analysis and Western blot and apoptosis assays demonstrated that low-dose 10-HCPT arrested Colo 205 cells in the G2 phase of the cell-cycle and triggered apoptosis through a caspase-3-dependent pathway. No acute toxicity was observed after an oral challenge of 10-HCPT in BALB/c-nude mice every 2 days.

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

References

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


Ping YH, Lee HC, Lee JY, et al. (2006). Anti-cancer effects of low-dose 10-hydroxycamptothecin in human colon cancer. Oncology Reports, 15(5), 1273-9.

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

Caffeic acid phenethyl ester (CAPE)

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

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

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

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

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

Multiple Immunomodulatory and Anti-inflammatory Activities

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

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

Breast Cancer

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

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

Prostate Cancer

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

EMT, Prostate Cancer

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

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

Cervical Cancer

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

Oral Cancer

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

Melanoma

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

References

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


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


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


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


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


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


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


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


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


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


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


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

Anti-cancer, Anti-cancer effect, apoptosis, Apoptotic, BAX, Breast cancer, CDC2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, chemo-sensitizing, Chemotherapy, Cytostatic, ER, G1, G2/M, Glioblastoma, H460, Liver cancer, Lung cancer, Oral cancer, p21, p53, PARP, PKC, radio-sensitizing, S, U87

Aloe-emodin (See also Emodin)

Cancer:
Nasopharyngeal., ER α degradation, Lung, breast, oral., glioblastoma, liver cancer prevention

Action: Cytostatic, radio-sensitizing, chemo-sensitizing

Nasopharyngeal Carcinoma

Aloe-emodin (AE), a natural., biologically active compound from Aloe vera leaves has been shown to induce apoptosis in several cancer cell lines in vitro. Investigation showed that AE induced G2/M phase arrest by increasing levels of cyclin B1 bound to Cdc2, and also caused an increase in apoptosis of nasopharyngeal carcinoma (NPC) cells, which was characterized by morphological changes, nuclear condensation, DNA fragmentation, caspase-3 activation, cleavage of poly (ADP-ribose) polymerase (PARP) and increased sub-G(1) population. Treatment of NPC cells with AE also resulted in a decrease in Bcl-X(L) and an increase in Bax expression.

Collectively, results indicate that the caspase-8-mediated activation of the mitochondrial death pathway plays a critical role in AE-induced apoptosis of NPC cells (Lin et al., 2010).

Glioblastoma

Aloe emodin arrested the cell-cycle in the S phase and promoted the loss of mitochondrial membrane potential in glioblastoma U87 cells that indicated the early event of the mitochondria-induced apoptotic pathway. It plays an important role in the regulation of cell growth and death (Ismail et al., 2013).

Breast Cancer

The anthraquinones emodin and aloe-emodin are also abundant in the rhizome Rheum palmatum and can induce cytosolic estrogen receptor α (ER α) degradation; it primarily affected nuclear ER α distribution similar to the action of estrogen when protein degradation was blocked. In conclusion, our data demonstrate that emodin and aloe-emodin specifically suppress breast cancer cell proliferation by targeting ER α protein stability through distinct mechanisms (Huang et al., 2013).

Lung Cancer

Photoactivated aloe-emodin induced anoikis and changes in cell morphology, which were in part mediated through its effect on cytoskeleton in lung carcinoma H460 cells. The expression of protein kinase Cδ (PKCδ) was triggered by aloe-emodin and irradiation in H460 cells. Furthermore, the photoactivated aloe-emodin-induced cell death and translocation of PKCδ from the cytosol to the nucleus was found to be significantly inhibited by rottlerin, a PKCδ-selective inhibitor (Chang et al., 2012).

Oral Cancer; Radio-sensitizing, Chemo-sensitizing

The treatment of cancer with chemotherapeutic agents and radiation has two major problems: time-dependent development of tumor resistance to therapy (chemoresistance and radioresistance) and nonspecific toxicity toward normal cells. Many plant-derived polyphenols have been studied intensively for their potential chemo-preventive properties and are pharmacologically safe.

These compounds include genistein, curcumin, resveratrol, silymarin, caffeic acid phenethyl ester, flavopiridol, emodin, green tea polyphenols, piperine, oleandrin, ursolic acid, and betulinic acid. Recent research has suggested that these plant polyphenols might be used to sensitize tumor cells to chemotherapeutic agents and radiation therapy by inhibiting pathways that lead to treatment resistance. These agents have also been found to be protective from therapy-associated toxicities.

Treatment with aloe-emodin at 10 to 40 microM resulted in cell-cycle arrest at G2/M phase. The alkaline phosphatase (ALP) activity in KB cells increased upon treatment with aloe-emodin when compared to controls. This is one of the first studies to focus on the expression of ALP in human oral carcinomas cells treated with aloe-emodin. These results indicate that aloe-emodin has anti-cancer effect on oral cancer, which may lead to its use in chemotherapy and chemo-prevention of oral cancer (Xiao et al., 2007).

Liver Cancer Prevention

In Hep G2 cells, aloe-emodin-induced p53 expression and was accompanied by induction of p21 expression that was associated with a cell-cycle arrest in G1 phase. In addition, aloe-emodin had a marked increase in Fas/APO1 receptor and Bax expression. In contrast, with p53-deficient Hep 3B cells, the inhibition of cell proliferation of aloe-emodin was mediated through a p21-dependent manner that did not cause cell-cycle arrest or increase the level of Fas/APO1 receptor, but rather promoted aloe-emodin-induced apoptosis by enhancing expression of Bax.

These findings suggest that aloe-emodin may be useful in liver cancer prevention (Lian et al., 2005).

References

Chang WT, You BJ, Yang WH, et al. (2012). Protein kinase C delta-mediated cytoskeleton remodeling is involved in aloe-emodin-induced photokilling of human lung cancer cells. Anti-cancer Res, 32(9):3707-13.

Huang PH, Huang CY, Chen MC, et al. (2013). Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition. Evid Based Complement Alternat Med, 2013:376123. doi: 10.1155/2013/376123.

Ismail S, Haris K, Abdul Ghani AR, et al. (2013). Enhanced induction of cell-cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin. J Asian Nat Prod Res.

Lian LH, Park EJ, Piao HS, Zhao YZ, Sohn DH. (2005). Aloe Emodin‐Induced Apoptosis in Cells Involves a Mitochondria‐Mediated Pathway. Basic & Clinical Pharmacology & Toxicology, 96(6):495–502.

Lin, ML, Lu, YC, Chung, JG, et al. (2010). Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer Letters, 291(1), 46-58. doi: 10.1016/j.canlet.2009.09.016.

Xiao B, Guo J, Liu D, Zhang S. (2007). Aloe-emodin induces in vitro G2/M arrest and alkaline phosphatase activation in human oral cancer KB cells. Oral Oncol, 43(9):905-10.

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

Alisol B Acetate

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

Action: Cytostatic, cytotoxic

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

Hepatocellular Carcinoma

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

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

Gastric Cancer

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

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

References

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

 

 

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

 

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

 

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

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

Oxymatrine or Compound Matrine (Ku Shen)

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

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

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

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

Indications: Pain and bleeding caused by cancer.

Dosage and usage:

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

Anti-cancer

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

Sarcoma

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

T Cell Leukemia

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

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

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

Osteosarcoma

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

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

Pancreatic Cancer

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

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

Rectal Carcinoma

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

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

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

Gastric Cancer

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

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

Adenoid Cystic Carcinoma

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

Breast Cancer; Chemotherapy

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

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

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

Lung cancer; Pleural Effusion

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

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

Gastric Cancer

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

Colorectal Cancer; Chemotherapy

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

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

NSCLC; Chemotherapy

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

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

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

Lung Adenocarcinoma

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

Liver Cancer

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

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

Chemotherapy

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

Colorectal Cancer, NSCLC, Breast Cancer; Chemotherapy

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

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

anti-tumor, apoptosis, CDK2, cell-cycle arrest, Cervical cancer, Chapter 8 Injectables and Cancer Research, Chemo-sensitizer, Chemotherapy, chemotherapy support, Cytostatic, Immune, induces apoptosis, inhibits proliferation, Liver cancer, Lung cancer, metastasis, radiotherapy, VEGFR

Cinobufacini Injection

Cancer: Liver, lung

Action: Chemo-sensitizer, chemotherapy support, cytostatic

Ingredients: chan su (Dried toad skin/Bufo bufo gargarizans)

TCM functions: Removing Toxin, reducing swelling, relieving pain.

Indications: Anti-tumor, immune enhancing and anti-viral effects, and can be used in middle and late-stage tumors, chronic hepatitis B.

Dosage and usage:

Intramuscular injection: 2-4 ml once, twice daily, 2-3 months as a course of treatment.

Cervical Cancer; Radiotherapy

Sixty patients with early cervical cancer were randomly divided into two groups. Twenty eight cases in treatment group were treated by intensity modulated radiation therapy combined with Brucea javanica oil emulsion injection. Thirty two cases in control group were treated only by intensity modulated radiation therapy. There was no significant difference between the two groups on the short-term  effect and lesion local control rate (P > 0.05). The 3-year overall survival rate in the treatment group was higher than that in control group (P<0.05). There was significant difference between the two groups on radiation proctitis (P<0.05).

Intensity modulated radiation therapy combined with Brucea javanica oil emulsion injection can improve efficacy and reduce adverse reactions in early cervical cancer, worthy of clinical application. 10-20 ml mixed with 500 ml of 5% glucose for slow intravenous drip. Four weeks as a course of treatment, and 1-2 days interval after each week”s treatment.

Cinobufacini Injection (CI) showed better tumor inhibition effects on tumor-bearing rats of with a “heat syndrome” constitution, indicating CI was of a “cold property”. It may potentially be used in tumor-bearing rats of a “heat syndrome” constitution (Wang et al., 2011).

Induces Apoptosis

Chan Su is a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toads, and has been used as an oriental drug for the treatment of a number of diseases, including cancer. In lung carcinoma A549 cells, treatment with the skin of Venenum Bufonis (SVB) resulted in the inhibition of cell growth and viability, and the induction of apoptosis.

SBV treatment induced the proteolytic activation of caspases and the concomitant degradation of poly(ADP-ribose)-polymerase and beta-catenin protein. Cleavage of Bid and a down-regulation of the inhibitor of apoptosis family proteins were also observed in SBV-treated A549 cells. Data from this study indicates that SVB induces the apoptosis of A549 cells through a signaling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways (Yun et al., 2009).

Blocks Metastasis

The effect of Cinobufacini injection on proliferation, heterogeneous adhesion, and invasiveness of human hepatoma HepG-2 cells co-cultured with human lymphatic endothelial cells (HLEC) was studied.

A co-culture system of human hepatoma HepG-2 cells and HLEC was established by means of Transwell chamber. Cell proliferation was analyzed by Trypan blue stain assay. MTT assay was used to observe the heterogeneous adhesion capacity of HepG-2 cells co-cultured with HLEC. Transwell invasion chamber was used to observe the invasiveness capacity of HepG-2 cells co-cultured with HLEC.

Cinobufacini Injection significantly inhibits proliferation, heterogeneous adhesion and invasiveness of hepG-2 cells co-cultured with HLEC in dose-dependent ways (all P0.05). Cinobufacini injection can inhibit the capability of proliferation, invasiveness and heterogeneous adhesion of HepG-2 cells, which might contribute to the inhibiting mechanisms of Cinobufacini injection on tumor metastasis (Fu, Gao, Tian, Chen, & Cui, 2013).

Inhibits Human Lymphatic Endothelial Cells (HLEC)

The effect of Cinobufacini injection on proliferation, migration and tubulin formation of human lymphatic endothelial cells (HLEC) was investigated.

Cell growth curve was used to observe the effect of Cinobufacini injection on the proliferation of HLEC; migration assay was used to observe the effect of Cinobufacini injection on the migration of HLEC; Matrigel assay was used to observe the effect of Cinobufacini injection on the tubulin formation of HLEC; Western blot was used to analyze the expression of VEGFR-3 and HGF in HLEC.

As the dosage of Cinobufacini injection increased (0.105, 0.21 and 0.42 µg/mL), so did the inhibition of HLCE. Cinobufacini injection demonstrated significant inhibition of HLEC proliferation (P < 0.05), migration (P < 0.05) and tubulin formation, in a dose-dependent manner (P < 0.05). Cinobufacini injection significantly decreased the expression of VEGFR-3 and HGF in HLEC, in a dose-dependent manner (P < 0.05).

Cinobufacini injection significantly inhibits HLEC proliferation, migration, and tubulin formation. The down-regulation of VEGFR-3 and HGF may contribute to the inhibitory effect of Cinobufacini injection on HLEC (Gao, Chen, Xiu, Fu, & Cui, 2013).

NSCLC; Chemotherapy

The efficacy and safety of Cinobufacini injection, combined with chemotherapy, as a treatment for advanced non-small-cell lung cancer (NSCLC) was investigated. Based on existing clinical information, a search of databases, such as Medline (1966-2011), Cochrane Library (2011, Issue 11), CNKI (1978-2011), VIP (1989-2011), Wanfang Data (1988-2011), CBMdisc (1978-2011) was done.

A total of seven RCTs of 498 patients were included. Meta-analysis results show that the experimental group and control group have significant differences in the response rate [RR=1.29, 95% CI (1.07, 1.56)], Karnofsky score [RR=1.86, 95% CI (1.14, 3.05)], weight change [RR=1.56, 95% CI (1.20, 2.03)], gastrointestinal side-effects [RR=0.72, 95% CI (0.53, 0.99)], neutropenia [RR=0.70, 95%CI(0.54, 0.91)], thrombocytopenia [RR=0.53, 95% CI (0.38, 0.75)], and renal function [RR=0.37, 95% CI (0.17, 0.79).

Cinobufacini, combined with chemotherapy, is suitable for advanced NSCLC by improving the response rate, increasing Karnofsky score, gaining weight and reducing major side-effects (Tu, Yin, & He, 2012).

Liver Cancer

The clinical effect of Cinobufacini injection, combined with transcatheter arterial chemoembolization (TACE), on treating primary liver cancer was investigated.

Seventy-eight patients with moderate and advanced primary liver cancer were randomly divided. The treatment group (n=38) was treated by Cinobufacini injection combined with TACE, and the control group (n=40), was treated by TACE only.

Quality of life of patients in the treatment group was significantly higher than that in control group. The 12 months survival rate of the treatment group was significantly higher than that of control group. There was no statistical difference in the rate of effectiveness between the two groups. Laboratory tests, after three cycles, in the treatment group were better than that of the control group, and the difference between the two groups was statistically significant.

Cinobufacini injection, combined with TACE, can decrease TACE induced liver damage, prolong survival time, and improve body immunity (Ke, Lu, & Li, 2011).

Hepatoma

Cinobufacini injection significantly inhibited HepG-2 cells proliferation in a dose and time-dependent manner. FCM analysis showed Cinobufacini injection induced cell-cycle arrest at the S phase. RT-PCR assay showed Cinobufacini injection down-regulated Cyclin A, and CDK2 expression at mRNA levels. Quantitative colorimetric assay showed Cinobufacini injection deceased Cyclin A/CDK2 activity in HepG-2 cells.

Cinobufacini injection can inhibit human hepatoma HepG-2 cells growth, induce cell apoptosis and induce cell-cycle arrest at the S phase. Its mechanism might be partly related to the down-regulation of Cyclin A, CDK2 mRNA expression, and inhibition of Cyclin A/CDK2 activity (Sun, Lu, Liang, & Cui, 2011).

Cell-cycle Arrest

Studies in China by Sun et al., (2011), Ke et al., (2011) and Tu et al., (2012) demonstrated that Cinobufacini Injection induced cell-cycle arrest, and could be used in the treatment of primary liver cancer, as well as in conjunction with chemotherapy in the treatment of non-small-cell lung cancer.

Caution

Resibufogenin (RBG), one of the major components in chan su, significantly affected all parameters of transmembrane action potential., induced delayed response after depolarization, and triggered arrhythmias in sheep and canine Purkinje fibers. Chan su toxicity carries a high mortality rate in the United States and this study focused upon the cardiac electrophysiological and electro-toxicity effects of RBG (Xie et al., 2000).

References

Fu, H.Y., Gao, S., Tian, L.L., Chen, X.Y., & Cui, X.N. (2013). Effect of Cinobufacini injection on proliferation and invasiveness of human hepatoma HepG-2 cells co-cultured with human lymphatic endothelial cells. The Chinese Journal of Clinical Pharmacology, 29(3), 199-201.


Gao, S., Chen, X.Y., Fu, H.Y., & Cui, X.Z. (2013). The effect of Cinobufacini injection on proliferation and tube-like structure formation of human lymphatic endothelial cells. China Oncology, 23(1), 36-41.


Ke, J, Lu, K., & Li, Y. (2011). Clinical observation of patients with primary liver cancer treated by Cinobufagin Injection combined with transcatheter arterial chemoembolization. Chinese Journal of Clinical Hepatology.


Sun, Y., Lu, X.X., Liang, X.M., & Cui, X.N. (2011). Impact of Cinobufacini injection on proliferation and cell-cycle of human hepatoma HepG-2 cells. The Chinese-German Journal of Clinical Oncology, 10(6), 321-324.


Tu, C., Yin, J., & He, J. Meta-analysis of Cinobufacini injection plus chemotherapy in the treatment of non-small-cell lung cancer. Anti-tumor Pharmacy, 2(1), 67-72.


Wang, S.S., Zhai, X.F., Li, B. (2011) Effect of cinobufacini injection on the tumor growth of tumor-bearing rats of different constitutions. Zhongguo Zhong Xi Yi Jie He Za Zhi, 31(8):1101-3.


Xie, J-T., Wang, Hs., Attele A.S., Yuan, C-S. (2000). Effects of Resibufogenin from Toad Venom on Isolated Purkinje Fibers. American Journal of Chinese Medicine, 28(2):187-196.


Yun, H.R., Yoo, H.S., Shin, D.Y., et al. (2009). Apoptosis induction of human lung carcinoma cells by Chan Su (Venenum Bufonis) through activation of caspases. J Acupunct Meridian Stud, 2(3):210-7. doi: 10.1016/S2005-2901(09)60057-1.

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

Camptothecin (CPT) & 10-hydroxycamptothecin (HCPT)

Cancer: Breast, colon

Action: Cytostatic

Breast Cancer

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

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

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

Colon Cancer

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

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

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

References

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


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

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

Ai Di Injection (ADI)

Cancers: Breast, colorectal., glioma, lung

Action: Chemo-sensitizer, cytostatic, radio-sensitizer

 

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

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

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

Dosage and usage:

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

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

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

Intervention treatment: 10 days as a course of treatment.

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

 

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

 

Glioma; Radio-sensitization

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

 

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

 

Breast Cancer

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

 

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

 

Colorectal Cancer; FOLFOX4

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

 

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

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

 

NSCLC

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

 

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

 

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

 

NSCLC; Meta-analysis

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

 

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

 

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

 

NSCLC; Neo-adjuvant Chemotherapy

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

 

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

 

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

 

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

 

References

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

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

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

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

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

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

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

Baicalin & Baicalein

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

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

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

Anti-cancer

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

Multiple Myeloma

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

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

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

Hepatoma

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

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

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

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

Ovarian Cancer

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

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

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

Breast Cancer

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

Breast Cancer, Cell Invasion

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

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

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

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

Oral Cancer

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

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

Anti-inflammatory

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

Angiogenesis Modulation

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

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

Colon Cancer

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

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

Cardio-protective

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

Prostate Cancer

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

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

Cancer: Acute lymphocytic leukemia, lymphoma and myeloma

Action: Cell-cycle arrest, induces apoptosis

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

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

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

Tanshinone II A & Tanshinone A (See also Cryptotanshinone)

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

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

Anti-cancer

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

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

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

Leukemia

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

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

Prostate Cancer

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

Gastric Cancer

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

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

Cell-cycle Arrest

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

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

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

Prostate Cancer, Chemo-sensitizer

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

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

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

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

Autophagic Cell Death, CSCs

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

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

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

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

Colorectal Cancer

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

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

Breast Cancer

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

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

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

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

Nasopharyngeal Carcinoma

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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