Nobiletin inhibits colitis‐associated colon carcinogenesis in mice (121.6)

Nobiletin is a major citrus flavonoid that has shown various health benefits. Herein, we investigated the inhibitory effects of nobiletin on colitis‐associated colon carcinogenesis in azoxymethane/Dextran Sulfate Sodium ‐treated mice. The results showed that oral administration of nobiletin significantly decreased colon tumor incidence by 42% and reduced colon tumor size by 37%. Immunohistochemical analysis demonstrated that nobiletin had significant anti‐proliferative and pro‐apoptotic effects in the colonic tumors. ELISA results showed that nobiletin significantly suppressed the expression levels of inflammatory cytokines IL‐1, IL‐6 and TNF‐ α in colonic tissues by 92%, 69% and 51%, respectively. HPLC analysis indicated that oral administration of nobiletin resulted in high levels of metabolites, i.e. 3'‐demethylnobiletin, 4'‐demethylnobiletin, and 3', 4'‐didemethylnobiletin in the colonic tissues. In contrast, the levels of nobiletin in the colon was 5‐10‐fold lower. Cell culture study showed that the three metabolites had much stronger anti‐proliferative and pro‐apoptotic effects on human colon cancer cells than nobiletin. Overall, our results demonstrated that oral administration of nobiletin significantly inhibited colitis‐associated colon carcinogenesis in mice and these effects can be attributed to the colonic metabolites of nobiletin that had potent anti‐carcinogenic effects in the colon. Grant Funding Source : Supported by NIH, AICR and USDA