The relationship between inflammation and the development of colorectal cancer has received considerable attention over the last decade. Novel agents with anti-inflammatory properties appear to have beneficial effects in reducing the risk of developing colorectal cancer. Resveratrol, a naturally occurring polyphenolic compound, has been studied extensively with considerable amounts of evidence demonstrating its efficacy as an anti-inflammatory and anti-cancer agent. Given the number and diversity of the reported protective roles of resveratrol, we used an unbiased systems approach to elucidate the underlying mechanisms of resveratrol's protection against colitis-induced colorectal cancer. Utilizing genomics, metabolomics and microbiome analysis in a pre-clinical model of colitis-induced colorectal carcinogenesis, we have linked the anti-inflammatory actions of resveratrol to both known targets and other novel potential molecular mechanisms.

In a study, we treated mice with chemical carcinogen azoxymethane (AOM) and then exposed the mice to colonic irritant dextran sodium sulfate (DSS) to induce colitis-associated colon carcinogenesis. We found that a diet enriched in resveratrol (300ppm) prevented polyp formation, as well as, prevented polyps from progressing to adenomacarcinomas. Resveratrol treatment promoted the early recovery of DSS-induced inflammation with less severity of leukocyte infiltration and lower levels of IL-6, IL-8, and IL-10. Interestingly, the level of IL-22, which contributes to host defense at mucosal surfaces, was also significantly reduced with resveratrol. The metabolomic profile of DSS-treated control animals showed an elevation of microbial derived metabolites in the serum, which was ameliorated with resveratrol treatment. Together, resveratrol appears to preserve the intestinal barrier during early inflammation.

Prior studies have shown resveratrol's role in inhibiting several key enzymes active during tumor progression. We have correlated such findings with metabolomic biomarkers. We found a significant reduction in arachidonic acid, the limiting reagent of pro-inflammatory enzyme Cyclooxygenase-2 (COX-2). We also saw a reduction in spermidine. This polyamine is a product of Ornithine decarboxylase (ODC) activity that promotes proliferation. We have linked some of these metabolomic changes to changes in gene expression.

These pre-clinical studies are consistent with that of previous studies and demonstrate the efficacy of resveratrol in preventing colitis associated colorectal cancer. A systems approach to study the chemopreventive efficacy of anti-inflammatory compounds like resveratrol may be an important paradigm for discovering the chemopreventive mechanisms of these agents.

Citation Format: Shakir M. Saud, Amiran Dzutsev, Giorgio Trinchieri, Nancy Colburn, Matthew R. Young, Young Kim. To dine with red wine: Systems approach to studying resveratrol's protection against inflammatory colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4118. doi:10.1158/1538-7445.AM2014-4118