Abstract A76: Diet versus drug paradigm for the prevention of colorectal cancer: Isorhamnetin and resveratrol versus sulindac and DFMO

Increase in polyamine synthesis and inflammation is associated with increased risk in colon carcinogenesis. In patients with a high risk for colon cancer a combination treatment with difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, and sulindac, a nonsteroidal anti-inflammatory drug, resulted in a synergistic reduction in adenoma recurrence. However, this drug combination has some toxicities and should be limited to those individuals with a positive benefit to risk ratio.

Bioactive food components have been shown to modulate inflammation and polyamine synthesis and can influence the risk of developing colon cancer with less toxicity. In this study we demonstrated that the chemopreventive activity of isorhamnetin (a plant flavonoid), and resveratrol (a naturally occurring polyphenolic compound) may mimic the effects of sulindac and DFMO. In a mouse model for colitis-associated colon carcinogenesis where mice are treated with the chemical carcinogen azoxymethane (AOM) and then exposed to colonic irritant dextran sodium sulfate (DSS), a diet enriched in isorhamnetin or resveratrol resulted in a reduction in tumor incidence by 22 and 29 percent, respectively. Furthermore, analysis of biomarkers revealed both anti-proliferative and anti-inflammatory properties of both isorhamnetin and resveratrol in vivo. More intriguingly, we found that isorhamnetin mimics sulindac activity by inhibiting Src kinase activity and interfering with Wnt/beta catenin signaling both in culture and in mice. In addition, our metabolomic analyses suggest that resveratrol mimics DFMO activity by inhibiting ornithine decarboxylase (ODC) activity in the mouse colon. Inhibition of ODC by resveratrol was confirmed in culture. It will be interesting to see if the combination of isorhamnetin and resveratrol will have a synergistic effect on prevention of colon cancer. These findings suggest that isorhamnetin and resveratrol could be used as a safer alternative to sulindac and DMFO for the prevention of colon cancer.

Citation Format: Shakir Saud, Young Kim, Gerd Bobe, Nancy H. Colburn, Matthew R. Young. Diet versus drug paradigm for the prevention of colorectal cancer: Isorhamnetin and resveratrol versus sulindac and DFMO. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A76.