Colorectal cancer is a preventable yet highly prevalent disease worldwide. Poor patient compliance with screening procedures increases the mortality due to colorectal cancer. There is an urgent need for chemopreventive measures for this tumor type. One of the most promising chemopreventives in recent years is the dietary polyphenol resveratrol (RSV). While RSV has shown effective anticancer properties in cellular and rodent models, one limit to its development as a drug is its extremely high metabolism and resultant low oral bioavailability. There is ample evidence for therapeutic efficacy of RSV despite its high metabolism. The pharmacologic effects of RSV metabolites have never been elucidated. The overall goal of this proposal is to characterize the pharmacology of the major conjugated metabolites of RSV, and to delineate the effect of RSV on conjugating enzyme expression and activity. This research will advance our knowledge of a potential new chemopreventive drug, RSV, its pharmacology, and its potential for drug-drug interactions. We hypothesize that RSV conjugation plays an important role in its therapeutic effects via either inactivation or production of active metabolites. RSV is additionally hypothesized to alter its own conjugation by inhibition or induction of xenobiotic conjugating enzymes.
Two specific aims are proposed: 1) Determine the pharmacologic activity of RSV conjugates, and 2) Characterize the effect of RSV on human uridine glucuronosyltransferase (UGT) and sulfotransferase (SULT) induction / inhibition. We will synthesize the major metabolites of RSV and test their role in cell proliferation with colon cancer cell lines (FHC controls, Caco-2, HT-29, and HCT-116) as our model. We will additionally evaluate changes in UGT / SULT protein expression and enzyme activity in human hepatocytes as well as colon cells upon treatment with RSV or its metabolites. Protein expression will be quantitated with western blot analysis, while enzyme activity will be characterized with specific substrates toward each isozyme. Taken together, these experiments will provide the first evaluation of the pharmacology of RSV metabolites, and the effect of RSV in regulation of enzymes responsible for its metabolism.
The studies proposed in this application will evaluate the efficacy of the dietary polyphenol resveratrol as a potential drug for colorectal cancer prevention. Knowledge of the efficacy of resveratrol and its breakdown products in the body will help develop resveratrol or similar chemicals as useful drugs. Our studies will also evaluate whether resveratrol can interact with co-administered drugs.
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| Iwuchukwu, Otito F; Tallarida, Ronald J; Nagar, Swati (2011) Resveratrol in combination with other dietary polyphenols concomitantly enhances antiproliferation and UGT1A1 induction in Caco-2 cells. Life Sci 88:1047-54 |
