Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Kohno, Hiroyuki; Tanaka, Takuji; Kawabata, Ken‐ichi; Hirose, Yoshinobu; Sugie, Shigeyuki; Tsuda, Hiroyuki; Mori, Hideki

doi:10.1002/ijc.10625

Cited by 134 publications

(89 citation statements)

References 33 publications

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“…In another similar but more detailed study, it was observed that silymarin administration through diet for 4 weeks either during or after carcinogen (Azoxymethane) exposure led to a significant reduction in the frequency of aberrant crypt foci formation. In long term experiment, silymarin significantly reduced the incidence and multiplicity of colonic adenocarcinomas when fed during initiation or post initiation phase of AOM-induced colon carcinogenesis (Kohno et al, 2002). Silymarin exerted these beneficial effects via the reduction of proliferating cell nuclear antigen (PCNA) positive cells and increase in the number of apoptotic cells.…”

Section: Colon Cancermentioning

confidence: 99%

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Kaur

Agarwal

2007

Toxicology and Applied Pharmacology

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Failure and high systemic toxicity of conventional cancer therapies have accelerated the focus on the search for newer agents, which could prevent and/or slow-down cancer growth and have more human acceptability by being less or non-toxic. Silymarin is one such agent, which has been extensively used since ages for the treatment of liver conditions, and thus has possibly the greatest patient acceptability. In recent years, increasing body of evidence has underscored the cancer preventive efficacy of silymarin in both in vitro and in vivo animal models of various epithelial cancers. Apart from chemopreventive effects, other noteworthy aspects of silymarin and its active constituent silibinin in cancer treatment include their capability to potentiate the efficacy of known chemotherapeutic drugs, as an inhibitor of multidrug resistance associated proteins, and as an adjunct to the cancer therapeutic drugs due to their organ-protective efficacy specifically liver, and immunostimulatory effects. Widespread use of silymarin for liver health in humans and commercial availability of its formulations with increased bioavailability, further underscore the necessity of carrying out controlled clinical trials with these agents in cancer patients. In this review, we will briefly discuss the outcomes of clinical trials being conducted by us and others in cancer patients to provide insight into the clinical relevance of the observed chemopreventive effects of these agents in various epithelial cancer models.

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Section: Colon Cancermentioning

confidence: 99%

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Kaur

Agarwal

2007

Toxicology and Applied Pharmacology

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“…A wide range of studies by us and others have shown strong cancer chemopreventive and anticancer efficacy of silibinin (or its crude form known as silymarin) in different animal tumor bioassay systems as well as in cell culture models of epithelial cancers such as skin (Katiyar et al, 1997;Zi et al, 1997;Ahmad et al, 1998;Lahiri-chatterjee et al, 1999), prostate (Zi et al, 1998b;Zi and Agarwal, 1999a;Dhanalakshmi et al, 2002;Singh et al, 2002a), breast (Zi et al, 1998a;Bhatia et al, 1999) and cervical (Bhatia et al, 1999) cancers. With regard to colon cancer, a recent study has shown cancer preventive effect of silymarin against azoxymethane-induced colon carcinogenesis in male F344 rats (Kohno et al, 2002); however, the underlying mechanism of action remains to be elucidated. In the present study, we employed human colon carcinoma HT-29 cells to investigate the anticancer effects of silibinin and associated molecular events.…”

Section: Introductionmentioning

confidence: 99%

Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells

et al. 2003

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Silymarin, a defined mixture of natural flavonoid, has recently been shown to have potent cancer chemopreventive efficacy against colon carcinogenesis in rat model; however, the mechanism of such efficacy is not elucidated. Here, using pure active agent in silymarin, namely silibinin, we show its antiproliferative and apoptotic effects, and associated molecular alterations in human colon carcinoma HT-29 cells. Silibinin treatment of cells at 50-100 lg/ml doses resulted in a moderate to very strong growth inhibition in a dose-and a time-dependent manner, which was largely due to a G0/G1 arrest in cell cycle progression; higher dose and longer treatment time also caused a G2/M arrest. In mechanistic studies related its effect on cell cycle progression, silibinin treatment resulted in an upregulation of Kip1/p27 and Cip1/p21 protein as well as mRNA levels, and decreased CDK2, CDK4, cyclin E and cyclin D1 protein levels together with an inhibition in CDK2 and CDK4 kinase activities. In other studies, we observed that G2/M arrest by silibinin was associated with a decrease in cdc25C, cdc2/p34 and cyclin B1 protein levels, as well as cdc2/p34 kinase activity. In the studies assessing biological fate of silibinin-treated cells, silibinin-induced cell cycle arrest and growth inhibition were not associated with cellular differentiation, but caused apoptotic death. The quantitative apoptosis analysis showed up to 15% apoptotic cell death after 48 h of silibinin treatment. Interestingly, silibinin-induced apoptosis in HT-29 cells was independent of caspases activation, as all caspases inhibitor did not reverse silibinin-induced apoptosis. This observation was further confirmed by the findings showing a lack in caspases activity increase and caspases and PARP cleavage as well as a lack in cytochrome c release in cytosol following silibinin treatment of HT-29 cells. Additional studies conducted in mice showed that silibinin doses found effective in HT-29 cells are achievable in plasma, which increases the significance of the present findings and their possible translation in in vivo anticancer efficacy of silibinin against colon cancer. Together, these results identify molecular mechanisms of silibinin efficacy as a cell cycle regulator and apoptosis inducer in human colon carcinoma HT-29 cells, and justify further studies to investigate potential usefulness of this nontoxic agent in colon cancer prevention and intervention.

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“…These molecules are active against tumours, platelet aggregation, viral infection, and allergic or inflammatory responses. Some of them have antioxidant effects (Kim et al, 1998;Jenab et al, 1999;Schmelz et al, 1999;Akao, 2000;Kim et al, 2000;Jeong et al, 2002;Kohno et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Genetic characterization of the β-glucuronidase enzyme from a human intestinal bacterium, Ruminococcus gnavus

2005

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b-Glucuronidase activity (encoded by the gus gene) has been characterized for the first time from Ruminococcus gnavus E1, an anaerobic bacterium belonging to the dominant human gut microbiota. b-Glucuronidase activity plays a major role in the generation of toxic and carcinogenic metabolites in the large intestine, as well as in the absorption and enterohepatic circulation of many aglycone residues with protective effects, such as lignans, flavonoids, ceramide and glycyrrhetinic acid, that are liberated by the hydrolysis of the corresponding glucuronides. The complete nucleotide sequence of a 4537 bp DNA fragment containing the b-glucuronidase locus from R. gnavus E1 was determined. Five ORFs were detected on this fragment: three complete ORFs (ORF2, gus and ORF3) and two partial ORFs (ORF4 and ORF5). The products of ORF2 and ORF3 show strong similarities with many b-glucoside permeases of the phosphoenolpyruvate : b-glucoside phosphotransferase systems (PTSs), such as Escherichia coli BglC, Bacillus subtilis BglP and Bacillus halodurans PTS Enzyme II. The product of ORF5 presents strong similarities with the amino-terminal domain of Clostridium acetobutylicum b-glucosidase (bglA). The gus gene product presents similarities with several known b-glucuronidase enzymes, including those of Lactobacillus gasseri (69 %), E. coli (61 %), Clostridium perfringens (59 %) and Staphylococcus aureus (58 %). By complementing an E. coli strain in which the uidA gene encoding the enzyme was deleted, it was confirmed that the R. gnavus gus gene encodes the b-glucuronidase enzyme. Moreover, it was found that the gus gene was transcribed as part of an operon that includes ORF2, ORF3 and ORF5.

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Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Cited by 134 publications

References 33 publications

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells

Genetic characterization of the β-glucuronidase enzyme from a human intestinal bacterium, Ruminococcus gnavus

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