5‐Demethylnobiletin inhibits colon carcinogenesis in azoxymethane/dextran sulfate sodium‐treated mice (123.3)

Abstract

Our previous studies have demonstrated inhibitory effects of 5‐demethylnobiletin (5DN, a unique citrus flavonoid) in cultured colon cancer cells. Herein, we determined effects of 5DN on colitis‐associated colon carcinogenesis in azoxymethane/Dextran Sulfate Sodium ‐treated mice. Our results demonstrated that oral administration of 5DN significantly lowered colon tumor incidence by 54% and decreased overall tumor size by 49%. immunohistochemical analysis showed that 5DN had strong anti‐proliferative and pro‐apoptotic effects on colonic tumors. ELISA results demonstrated that 5DN suppressed the levels of IL‐1 and IL‐6 in colonic tissue by 89% and 87%. Immunoblot assay showed that 5DN significantly decreased the expression level of iNOS and COX‐2 in mice colon. HPLC analysis showed that oral administration of 5DN resulted in high levels of 5DN and its metabolites, i.e. 5,3'‐didemethylnobiletin, 5,4'‐didemethylnobiletin, and 5,3', 4’‐tridemethylnobiletin in the colonic tissues. Cell culture study showed that these metabolites, especially 5,3’‐didemethylnobiletin had much stronger inhibition on human colon cancer cells than 5DN. Flowcytometry analysis indicated that 5DN and its metabolites induced extensive cell cycle arrest and apoptosis. In conclusion, our results demonstrated that oral administration of 5DN significantly inhibited colitis‐associated colon carcinogenesis in mice and these effects can be partially attributed to the colonic metabolites of 5DN.Grant Funding Source: This work was supported by funding from NIH, AICR and USDA.