Category Archives: Colon Cancer or Colorectal cancer

all, Colon Cancer or Colorectal cancer, Leukemia, Melanoma

Cinnamaldehyde

Cancer: Leukemia, melanoma, colorectal

Action: Apoptosis, AP-1 transcriptional activity

Cinnamaldehyde is an active compound isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which has been shown to inhibit tumor cell proliferation. In this study, Ka et al., (2003) investigated the effects of cinnamaldehyde on the cytotoxicity, induction of apoptosis and the putative pathways of its actions in human promyelocytic leukemia cells. Using apoptosis analysis, measurement of reactive oxygen species (ROS), and assessment of mitochondrial membrane potentials (Δψm), they show that cinnamaldehyde is a potent inducer of apoptosis and that it transduces the apoptotic signal via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. Taken together, the data indicate that cinnamaldehyde induces the ROS-mediated mitochondrial permeability transition and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of cinnamaldehyde.

Source
Ka H, Park H-J, Jung H-J, et al. Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells. Cancer Letters. Volume 196, Issue 2, 10 July 2003, Pages 143–152. doi:10.1016/S0304-3835(03)00238-6

To investigate the anti-tumor activities of several cinnamaldehyde derivatives, we compared the inhibitory effect of cinnamaldehyde derivatives on cell growth and AP-1 transcriptional activity in SW620 human colon cancer cells since AP-1 is a transcriptional factor implicated to control cancer cell growth. In further studies on the mechanism, Lee et al., (2007) found that consistent with the inhibitory effect on cell growth, 2′-hydroxycinnamaldehyde (HCA) dose-dependently (0 – 20 μg/ml) inhibited DNA binding activity of AP-1 accompanied with down regulation of c-Jun and c-Fos expressions. HCA also induced apoptotic cell death as well as expression of the apoptosis-regulating gene caspase-3, but inhibited the anti-apoptosis regulating gene bcl-2 in a dose-dependent manner. These results suggested that HCA has the most potent inhibitory effect against human colon cancer cell growth, and AP-1 may be an important target of HCA.

Source
Lee CW, Lee SH, Lee JW, et al. 2-Hydroxycinnamaldehyde Inhibits SW620 Colon Cancer Cell Growth Through AP-1 Inactivation. Journal of Pharmacological Sciences. Vol. 104 (2007) No. 1 P 19-28. http://doi.org/10.1254/jphs.FP0061204

cancer, Chapter 8 Injectables and Cancer Research, Colon Cancer or Colorectal cancer

Carnosic Acid

Cancer: Colorectal

Action: suppresses carcinogenesis

A study by Kim et al., (2014) determined the efficacy of carnosic acid (CA) for suppressing colon carcinogenesis associated with excess adiposity. The proliferation of HT-29 cells co-cultured with 3T3L1 cells was significantly higher than proliferation of control cells (p<0.05). CA treatment suppressed the growth of co-cultured HT-29 cells through cell cycle arrest and enhanced apoptosis by inhibiting leptin receptor (Ob-R) signaling including Akt and ERK phosphorylation. CA supplementation in vivo decreased the number of colon tumors and reduced circulating concentrations of leptin, adiponectin, insulin, and IGF-1. Colonic expression of Ob-R, insulin receptor (IR), p-Akt, p-ERK, Bcl-x,L and cyclinD1 protein was also suppressed in animals fed CA.

CA appears to alleviate adipocity-related acceleration of colon tumor formation.

Carnosic acid is a natural benzenediol abietane diterpene found in rosemary (Rosmarinus officinalis) and common sage (Salvia officinalis). Dried leaves of rosemary or sage contain 1.5 to 2.5% carnosic acid.

Source

Kim Y-J, Kim J-S, Seo Y-R, et al. Carnosic acid suppresses colon tumor formation in association with anti-adipogenic activity. Molecular Nutrition & Food Research. 2014 DOI: 10.1002/mnfr.201400293

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

Wogonin

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

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

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

Breast Cancer; ER+ & ER-

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

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

Neurotransmitter Action

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

Anti-metastasic

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

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

Anti-tumor and Anti-metastatic

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

Anti-inflammatory

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

Hypoxia-Induced Drug Resistance (MDR)

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

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

NSCLC

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

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

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

Colon Cancer

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

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

Breast

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

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

Chemoresistance; Cervical Cancer, NSCLC

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

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

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

References

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


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


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


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


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


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


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


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


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


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

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

 

 

 

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

Theaflavin-2

Cancer: none noted

Action: Anti-inflammatory, induces apoptosis

Apoptosis

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

Reference

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

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

Tetrandrine

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

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

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

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

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

Leukemia

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

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

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

MDR, Breast Cancer

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

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

Leukemia, MDR

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

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

Tamoxifen

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

Colon Cancer

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

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

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

Renal Cancer

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

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

Steamed American Ginseng Berry Ginsenosides

Cancer: Colorectal cancer

Action: Cell-cycle arrest, induces apoptosis

Research

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

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

References

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


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

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

Sophoridine (See also oxymatrine,Matrine)

Cancer: Colorectal, lung

Action: Cell-cycle arrest

Cell-cycle Arrest

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

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

Colorectal Cancer

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

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

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

References

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


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


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

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

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

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

Action: Scutellaria Anti-cancer, cell-cycle arrest

Malignant Glioma, Breast Carcinoma and Prostate Cancer

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

Anti-Cancer

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

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

Colon

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

References

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


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

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

Sanguinarine (See also chelerythrine)

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

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

AR+/AR- Prostate Cancer

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

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

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

Breast Cancer

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

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

Leukemia

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

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

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

T-lymphoblastic Leukemia

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

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

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

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

Colorectal Cancer

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

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

Bladder Cancer

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

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

Melanoma

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

References

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


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


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


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


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


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


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


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

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

RG3 (See also Ginsenosides)

Cancer: Glioblastoma, prostate, breast, colon

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

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

Angiosuppressive Activity

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

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

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

Glioblastoma

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

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

MDR/Enhanced Paclitaxel Absorption

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

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

Prostate Cancer

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

Enhances Chemotherapy

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

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

Colon Cancer

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

Anti-metastatic

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

References

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


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


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


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


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


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


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


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

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

Resveratrol 98%

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

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

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

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

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

Breast

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

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

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

Chemotherapy-Induced Cytotoxicity

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

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

Radio-sensitizer/Lung Cancer

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

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

Lymphoma

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

Skin Cancer

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

Prostate Cancer

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

Breast Cancer

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

References

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, Immune, increased QoL, metastasis, radiotherapy, Raises immune function, Rectal cancer

Quxie Extract (QXC)

Cancer: Colorectal

Action: Raises immune function, increased QoL

Colorectal Carcinoma

Forty patients with advanced colorectal carcinoma were observed in a randomized controlled clinical trial (RCT). Out of them, the 37 evaluable patients were assigned into the treatment group (18 patients) and the control group (19 patients). They were all treated by the routine treatment for cancer, including chemotherapy and radiotherapy, while those in the treatment group were administered with QXC additionally. The scores of TCM symptom, QOF and KPS in the treatment group were 15.59 +/- 3.78, 54.06 +/- 3.96 and 64.71 +/- 6.24 before treatment, and 10.53 +/- 5.57, 58.65 +/- 4.03, 69.41 +/- 4.29 after treatment, respectively, showing significant improvement (P<0.05).

While the three scores in the control group were 16.11 +/- 3.99, 54.06 +/- 4.39 and 64.44 +/- 5.11 before treatment, and 19.61 +/- 7.78, 50.17 +/- 8.26 and 60.00 +/- 9.70 after treatment, respectively, showing a statistically significant worsening tendency in the latter two (P <0.05). QXC can reduce the FR, prolong the ST, mST, mCFPT, and improve the QOF in patients with advanced colorectal carcinoma (Yang et al., 2008).

Forty four patients chosen from 48 patients with colorectal cancer at post-operational period (with 2 dropped out and 2 loss of follow-up) were assigned into two groups (A and B) according to randomized block design and received intervention treatment with QXC and placebo, respectively, which started after terminating the post-operational adjuvant treatment and lasted for 6 m. Out of the 44 patients, 28 were of stage H (15 in Group A and 13 in Group B) and 16 of stage Ill (8 in Group A and 8 in Group B). The relapse-metastasis (R-M) rate, median time of R- M, changes of symptoms, Karnofsky (KPS) score and immune function before and after intervention, as well as the safety of QXC, were observed.

The symptoms and KPS score in Group A were obviously better (P< 0.05), with improvement in B lymphocyte (P< 0.05) superior to that in Group B. No obvious adverse reaction to QXC was found. QXC might be effective in delaying the R-M of colorectal cancer, but the ultimate confirmation only could be obtained through 1– 2 y observation. Post-operational intervention with QXC in patients with colorectal cancer could apparently improve the quality of life and raise the immune function of patients; it is safe and might have some clinical significance in preventing the R-M of cancer (Yang et al., 2007).

Formula

Semen Crotonis (ba dou), Fructus Evodiae Rutaecarpae (wu zhu yu), Rhizoma Zingiberis Officinalis (gan jiang), Cortex Cinnamomi Cassiae (rou gui), Radix Aconiti Carmichaeli (chuan wu), Rhizoma Pinelliae Ternatae (ban xia), Exocarpium Citri Erythrocarpae (ju hong)

References

Yang YF, Xu Y, Wu Y, Wang L, Li Z, Zhang L, Zhu Y, Guo Z, Guo Q, Yan X. (2007). Clinical Randomized Double-blinded Controlled Study on Quxie Capsule in Reducing Post-operational Relapse and Metastasis of Colorectal Cancer. Zhong Guo Zhong Xi Yi Jie He Za Zhi, 27(10):879-892.


Yang Y, Chen Z, Xu Y, Wu Y. Wu X, Zhu Y, Li P, Shudi G. (2008). Randomized Controlled Study on Effect of Quxie Capsule on the Median Survival Time and Qualify of Life in Patients with Advanced Colorectal Carcinoma. Zhong Guo Zhong Xi Yi Jie He Za Zhi, 28(2):111-114.

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

Puerarin

Cancer: Colon, breast, acute myeloid leukemia

Action: MDR, aromatase inhibition, induces apoptosis

Induces Apoptosis, Colorectal Cancer

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

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

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

Induces Apoptosis, Breast Cancer

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

Breast Cancer, MDR

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

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

Acute Myeloid Leukemia (AML)

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

Aromatase Inhibition

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

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

References

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


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


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


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


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

Akt, Anti-cancer, anti-inflammatory, anti-inflammatory and anti-oxidant, Anti-metastatic, anti-metastatic effect, anti-oxidant, anti-proliferative, c-Myc, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, chemo-preventive activity, Colon Cancer or Colorectal cancer, ERK, ERK1, FAK, Fibrosarcoma, HCT-116, metastasis, PI3K, PI3K/Akt, Pinus genus, Rectal cancer, Sarcoma

Pinosylvin

Cancer: Colorectal, lung

Action: Anti-cancer, anti-inflammatory and anti-oxidant, chemo-preventive, anti-metastatic effect

Pinosylvin is a naturally occurring chemo-preventive trans-stilbenoid mainly found in plants of the Pinus genus (Pinus (L.) and Gnetum cleistostachyum (C. Y. Cheng)).

Anti-cancer, Anti-inflammatory and Anti-oxidant

Stilbenes are small molecular weight (approximately 200-300 g/mol), naturally occurring compounds and are found in a wide range of plant sources, aromatherapy products, and dietary supplements. These molecules are synthesized via the phenylpropanoid pathway and share some structural similarities to estrogen. Upon environmental threat, the plant host activates the phenylpropanoid pathway and stilbene structures are produced and subsequently secreted. Stilbenes act as natural protective agents to defend the plant against viral and microbial attack, excessive ultraviolet exposure, and disease. Stilbene compounds, piceatannol, pinosylvin, rhapontigenin, and pterostilbene possess potent anti-cancer, anti-inflammatory and anti-oxidant activities (Roupe et al., 2006).

Colorectal

Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, has exhibited a potential cancer chemo-preventive activity. The anti-proliferative activity of pinosylvin was investigated in human colorectal HCT 116 cancer cells.

Pinosylvin was also found to attenuate the activation of proteins involved in focal adhesion kinase (FAK)/c-Src/extracellular signal-regulated kinase (ERK) signaling, and phosphoinositide 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3β (GSK-3β) signaling pathway. Subsequently, pinosylvin suppressed the nuclear translocation of β-catenin, one of downstream molecules of PI3K/Akt/GSK-3β signaling, and these events led to the sequential down-regulation of β-catenin-mediated transcription of target genes including BMP4, ID2, survivin, cyclin D1, MMP7, and c-Myc. These findings demonstrate that the anti-proliferative activity of pinosylvin might be associated with the cell-cycle arrest and down-regulation of cell proliferation regulating signaling pathways in human colorectal cancer cells (Park et al., 2013).

Anti-metastatic

Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, exhibits a potential cancer chemo-preventive activity and also inhibits the growth of various human cancer cell lines via the regulation of cell-cycle progression. Pinosylvin suppressed the expression of matrix metalloproteinase (MMP)-2, MMP-9 and membrane type 1-MMP in cultured human fibrosarcoma HT1080 cells. Park et al. (2012) found that pinosylvin inhibited the migration of HT1080 cells in colony dispersion and wound healing assay systems.

The analysis of tumor in lung tissues indicated that the anti-metastatic effect of pinosylvin coincided with the down-regulation of MMP-9 and cyclooxygenase-2 expression, and phosphorylation of ERK1/2 and Akt. These data suggest that pinosylvin might be an effective inhibitor of tumor cell metastasis via modulation of MMPs.

References

Park EJ, Park HJ, Chung HJ, et al. (2012). Anti-metastatic activity of pinosylvin, a natural stilbenoid, is associated with the suppression of matrix metalloproteinases. J Nutr Biochem, 23(8):946-52. doi: 10.1016/j.jnutbio.2011.04.021.


Park EJ, Chung HJ, Park HJ, et al. (2013). Suppression of Src/ERK and GSK-3/ β-catenin signaling by pinosylvin inhibits the growth of human colorectal cancer cells. Food Chem Toxicol, 55:424-33. doi:10.1016/j.fct.2013.01.007.


Roupe KA, Remsberg CM, Yá–ez JA, Davies NM. (2006). Pharmacometrics of stilbenes: seguing towards the clinic. Curr Clin Pharmacol, 1(1):81-101.

Anti-cancer, anti-inflammatory, anti-oxidative, anti-proliferative, apoptosis, Apoptotic, Breast cancer, Caco-2,HCT-116, CDC2, CDK, Chapter 7 Isolates and Cancer Research, chemo-preventive, Colon Cancer or Colorectal cancer, COX-2, Esophageal cancer, growth-inhibitory, IKK, Immunomodulatory, inflammation, p65, Pro-apoptotic, S, TNF, Vaccinium genus

Piceatannol

Cancer: Esophageal, colorectal, breast

Action: Anti-inflammatory, anti-oxidative

Piceatannol, a naturally occurring analogue of resveratrol found in certain plants and berries of the Vaccinium genus, including Picea abies [(L.) H.Karst.], Aiphanes horrida [(Jacq.) Burret], Gnetum cleistostachyum (C. Y. Cheng), Vaccinium arboretum (Marshall), Vaccinium angustifolium (Aiton) and Vaccinium corymbosum (L.). It was previously identified as the active ingredient in herbal preparations in folk medicine. Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. It is isolated from various types of berries, grapes, rhubarb and sugar cane.

It has been shown that a diet containing freeze-dried black raspberries (BRB) inhibits the development of chemically-induced cancer in the rat esophagus. To provide insights into possible mechanisms by which BRB inhibit esophageal carcinogenesis, an ethanol (EtOH) extract of BRB was evaluated, and two component anthocyanins (cyanidin-3-O-glucoside and cyanidin-3-O−rutinoside) in BRB, for their effects on growth, apoptosis, and gene expression in rat esophageal epithelial cell lines. The EtOH extract and both anthocyanins selectively caused significant growth inhibition and induction of apoptosis in a highly tumorigenic cell line (RE-149 DHD) but not in a weakly tumorigenic line (RE-149).

The growth-inhibitory and pro-apoptotic effects were enhanced by the daily addition of the EtOH extract and the anthocyanins to the medium.

Esophageal Cancer

This differential effect may have been related to the relative amounts of anthocyanins in the extract vs.when they were added individually to the medium. It was hence concluded that the selective effects of the EtOH extract on the growth and apoptosis of highly tumorigenic rat esophageal epithelial cells in vitro may be due to preferential uptake and retention of its component anthocyanins, and this may also be responsible for the greater inhibitory effects of freeze-dried whole berries on tumor cells in vivo (Schwartz et al., 2009).

Colorectal

The effects of piceatannol on growth, proliferation, differentiation and cell-cycle distribution profile of the human colon carcinoma cell line Caco-2 were investigated. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed.

Determination of cell-cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were down-regulated. The abundance of p27Kip1 was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 µmol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemo-preventive or anti-cancer agent (Wolter et al., 2002).

Anti-inflammatory

Treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-κB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF- κB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-κB activated by H2O2, PMA, LPS, okadaic acid, and ceramide.

Piceatannol abrogated the expression of TNF-induced NF-κB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, it was found that piceatannol inhibited TNF-induced IκBα phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IκBα kinase activation, but had no significant effect on IκBα degradation. Piceatannol inhibited NF-κB in cells with deleted Syk, indicating the lack of involvement of this kinase.

Overall, these results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF- κB activation induced by various inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation (Ashikawa et al., 2002).

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal up-regulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3',5'-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and anti-oxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell-cycle progression. The effect of piceatannol was examined on the activation of the nuclear transcription factor NF-κB, one of the major transcription factors that regulate pro-inflammatory COX- 2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol- 13-acetate (TPA).

When pre-treated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-κB DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPAinduced phosphorylation and degradation of IκBα as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-κB. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pre-treatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-κB DNA binding activity, suggesting that piceatannol may directly modify NF-kB (Liu et al., 2009).

Breast Cancer

Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene; PIC) exhibits immunosuppressive and anti-tumorigenic activities in several cell lines, and it was found that PIC inhibited migration and anchorage-independent growth of human mammary epithelial cells (MCF-10A) treated with the prototypic tumor promoter, 12-O-tetradecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-κB and expression of cyclooxygenase-2 (COX-2) in MCF-10A cells. It was speculated that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKβ, thereby inhibiting its catalytic activity.

Results show that direct modification of IKKβ by PIC, presumably at the cysteine 179 residue, blocks NF-κB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells (Son et al., 2010).

References

Ashikawa K, Majumdar S, Banerjee S, et al. (2002). Piceatannol inhibits TNF-induced NF- κB activation and NF- κ B-mediated gene expression through suppression of IκBα kinase and p65 phosphorylation. The Journal of Immunology, 169(11):6490-7.


Liu D, Kim DH, Park JM. (2009). Piceatannol Inhibits Phorbol Ester-Induced NF- κ B Activation and COX-2 Expression in Cultured Human Mammary Epithelial Cells. Nutrition and Cancer, 61(6):855–63. doi: 10.1080/01635580903285080.


Schwartz SJ and Stoner GD. (2009). Black Raspberry Components Inhibit Proliferation, Induce Apoptosis, and Modulate Gene Expression in Rat Esophageal Epithelial Cells. Nutrition and Cancer, 61(6):816–26. doi: 10.1080/01635580903285148


Son PS, Park SA, Na HK, et al. (2010). Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF- κ B activation and cyclooxygenase-2 expression in human breast epithelial cells: cysteine 179 of IKK β as a potential target. Carcinogenesis, 31(8):1442-1449. doi: 10.1093/carcin/bgq099.


Wolter F, Clausnitzer A, Akoglu B and Stein J. (2001). Down-regulation of the cyclin D1/Cdk4 complex occurs during resveratrol-induced cell-cycle arrest in colon cancer cell lines. J. Nutr, 132(2):298-302.

ameliorated myelosuppression, anti-apoptotic, apoptosis, Apoptotic, BAX, Bcl-2, Bcl-xL, c-Jun, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Colon Cancer or Colorectal cancer, EP2, EP4, ERK, Gastric cancer or Stomach cancer, HepG2, SMMC-7721, HT29, JNK, Liver cancer, MDR, Multi-Drug Resistance, Multi-drug resistance, p38, Paeonia suffruticosa, PCNA, PGE2, Radio-protective, radio-protective effect, Rectal cancer, ROS, SGC7901/VCR

Paeoniflorin

Cancer: Hepatocellular carcinoma, colorectal, liver

Action: Radio-protective, ameliorated myelosuppression, MDR

Radio-protective

The radio-protective effect of paeoniflorin (PF), a main bioactive component in the traditional Chinese herb peony, on irradiated thymocytes and the possible mechanisms of protection have been investigated. Ionizing radiation can induce DNA damage and cell death by generating reactive oxygen species (ROS).

It was found 60Co γ-ray irradiation increased cell death and DNA fragmentation in a dose-dependent manner while increasing intracellular ROS. Pre-treatment of thymocytes with PF (50–200 µg/ml) reversed this tendency and attenuated irradiation-induced ROS generation. Hydroxyl-scavenging action of PF in vitro was detected through electron spin resonance assay. Several anti-apoptotic characteristics of PF, including the ability to diminish cytosolic Ca2+ concentration, inhibit caspase-3 activation, and up-regulate Bcl-2 and down-regulate Bax in 4 Gy-irradiated thymocytes, were determined.

Extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 kinase, were activated by 4 Gy irradiation, with their activation partly blocked by pre-treatment of cells with PF. The presence of ERK inhibitor PD98059, JNK inhibitor SP600125 and p38 inhibitor SB203580 decreased cell death in 4 Gy-irradiated thymocytes. These results suggest PF protects thymocytes against irradiation-induced cell damage by scavenging ROS and attenuating the activation of the mitogen-activated protein kinases (Li et al., 2007).

Liver Cancer

Prostaglandin E2 (PGE2) has been shown to play an important role in tumor development and progression. PGE2 mediates its biological activity by binding any one of four prostanoid receptors (EP1 through EP4). Paeoniflorin, a monoterpene glycoside, significantly inhibited the proliferation of HepG2 and SMMC-7721 cells stimulated by butaprost at multiple time points (24, 48, and 72 hours). Paeoniflorin induced apoptosis in HepG2 and SMMC-7721 cells, which was quantified by annexin-V and propidium iodide staining. Our results indicate that the expression of the EP2 receptor and Bcl-2 was significantly increased, whereas that of Bax and cleaved caspase-3 was decreased in HepG2 and SMMC-7721 cells.

Paeoniflorin, which may be a promising agent in the treatment of liver cancer, induced apoptosis in hepatocellular carcinoma cells by down-regulating EP2 expression and also increased the Bax-to-Bcl-2 ratio, thus up-regulating the activation of caspase-3 (Hu et al., 2013).

Colorectal Cancer

Results showed that positive cells of Proliferating Cell Nuclear Antigen (PCNA) in paeoniflorin (PF) and docetaxel-treated group was decreased to 30% and 15% respectively, compared with control group of tumors. But apoptosis cells in docetaxel treated groups studied by TUNEL is increased to 40 ± 1.2% and 30 ± 1.5% respectively, compared with 24 ± 2.3% in negative control. Furthermore, the efficiency of tumor-bearing mice treated by PF was superior to docetaxel in vivo. Overall, PF may be an effective chemo-preventive agent against colorectal cancer HT29 (Wang et al., 2012).

Ameliorates Myelosuppression

The administration of paeoniflorin and albiflorin (CPA) extracted from Paeonia radix, significantly ameliorated myelosuppression in all cases. For the X-ray irradiated mice and the chemotherapy treated mice and rabbits, high dosages of CPA resulted in the recovery of, respectively, 94.4%, 95.3% and 97.7% of hemoglobin content; 67.7%, 92.0% and 94.3% of platelet numbers; 26.8%, 137.1% and 107.3% of white blood cell counts; as well as a reversal in the reduction of peripheral differential white blood cell counts.

There was also a recovery of 50.9%, 146.1% and 92.3%, respectively, in the animals' relative spleen weight. Additionally, a recovery of 35.7% and 87.2% respectively in the number of bone marrow nucleated cells was observed in the radio- and chemo -therapy-treated mice. Bone marrow white blood cell counts also resumed to normal levels (Xu et al., 2011).

MDR

Studies have shown that NF-κB activation may play an essential role in the development of chemotherapy resistance in carcinoma cells. Paeonißorin, a principal bioactive component of the root of Paeonia lactißora, has been reported to exhibit various pharmacological effects. In the present study, Fanh et al. (2012) reported for the first time that paeoniflorin at non-toxic concentrations may effectively modulate multi-drug resistance (MDR) of the human gastric cancer cell line SGC7901/vincristine (VCR) via the inhibition of NF-κB activation and, at least partly, by subsequently down-regulating its target genes MDR1, BCL-XL and BCL-2.

References

Fang S, Zhu W, Zhang Y, Shu Y, Liu P. (2012). Paeoniflorin modulates Multi-drug resistance of a human gastric cancer cell line via the inhibition of NF- κB activation. Mol Med Rep, 5(2):351-6. doi: 10.3892/mmr.2011.652.


Hu S, Sun W, Wei W, et al. (2013). Involvement of the prostaglandin E receptor EP2 in paeoniflorin-induced human hepatoma cell apoptosis. Anti-cancer Drugs, 24(2):140-9. doi: 10.1097/CAD.0b013e32835a4dac.


Li CR, Zhou Z, Zhu D, et al. (2007). Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. The International Journal of Biochemistry & Cell Biology, 39(2):426–438


Wang H, Zhou H, Wang CX, et al. (2012). Paeoniflorin inhibits growth of human colorectal carcinoma HT 29 cells in vitro and in vivo. Food Chem Toxicol, 50(5):1560-7. doi: 10.1016/j.fct.2012.01.035.


Xu W, Zhou L, Ma X, et al. (2011). Therapeutic effects of combination of paeoniflorin and albiflorin from Paeonia radix on radiation and chemotherapy-induced myelosuppression in mice and rabbits. Asian Pac J Cancer Prev, 12(8):2031-7.

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-metastatic, apoptosis, Breast cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, CSCs, CT-26, Down-regulates, down-regulates MMP-9, MCF-7, MDR, metastasis, Rectal cancer

Norcantharidin (NCTD)

Cancer: Colorectal., CSCs, breast

Action: Anti-metastatic, MDR

Norcantharidin is a metastatic inhibitor derived from cantharidin, which is found in many species of blister beetles, including Mylabris phalerata (Pall.) and Lytta vesicatoria (Linnaeus).

Norcantharidin (NCTD) is a small-molecule metastatic inhibitor without renal toxicity derived from a renal toxic compound cantharidin, which is found in blister beetles (Mylabris phalerata Pall.), commonly used in traditional Chinese medicine.

Colorectal Cancer; Anti-metastatic

The aim of this study was to clarify the transcriptional regulation of MMP-9 gene by NCTD in colorectal cancer CT-26 cells. NCTD not only down-regulated MMP-9 mRNA and protein expression, but also inhibited gelatinase activity in a concentration- and time-dependent manner. Evidence by electrophoretic mobility shift assay demonstrated that NCTD inhibited the DNA-binding activity of Sp1. In addition, the increase effect of NF-kappaB-luciferase activity by NCTD may include the up-expression of nuclear STAT1 and result in competitive suppression of NF-kappaB-binding activity in MMP-9 promoter. In conclusion, the metastasis inhibitor NCTD down-regulates MMP-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer CT26 cells (Chen et al., 2009).

MDR; Cancer Stem Cells

Hsieh et al. (2013) investigated the modulation of self-renewal pathways and MDR in CSCs by NCTD. They suggest that using NCTD to develop more effective strategies for cancer treatment to reduce resistance and recurrence.

Breast Cancer

Cantharidin and norcantharidin induced apoptosis and repressed MCF-7 cell growth, adhesion and migration. They repressed MCF-7 cell adhesion to platelets through down-regulation of α2 integrin, an adhesion molecule present on the surface of cancer cells. The repression of α2 integrin expression was found to be executed through the protein kinase C pathway, the activation of which could have been due to PP2A inhibition (Shou et al. 2013).

References

Chen YJ, Chang WM, Liu YW, et al. (2009). A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells. Chem Biol Interact., 181(3):440-6.


Hsieh CH, Chao KS, Liao HF, Chen YJ. (2013). Norcantharidin, Derivative of Cantharidin, for Cancer Stem Cells. Evid Based Complement Alternat Med, 2013;2013:838651.


Shou LM, Zhang QY, Li W, et al. (2013). Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent down-regulation of α 2 integrin. Oncol Rep. doi: 10.3892/or.2013.2601.

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.