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Chemopreventive effects of nobiletin and its colonic metabolites on colon carcinogenesis
Author(s) -
Wu Xian,
Song Mingyue,
Wang Minqi,
Zheng Jinkai,
Gao Zili,
Xu Fei,
Zhang Guodong,
Xiao Hang
Publication year - 2015
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201500378
Subject(s) - azoxymethane , nobiletin , colorectal cancer , apoptosis , cell growth , colitis , carcinogenesis , oral administration , pharmacology , medicine , chemistry , cancer research , cancer , biochemistry , flavonoid , antioxidant
Scope Nobiletin (NBT) is a major citrus flavonoid with various health benefits. Herein, we investigated the colon cancer chemopreventive effects of NBT and its colonic metabolites in a colitis‐associated colon carcinogenesis mouse model as well as in human colon cancer cell models. Methods and results In azoxymethane/dextran sulfate sodium treated mice, oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant antiproliferative, proapoptotic, and anti‐inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites, i.e. 3′‐demethylnobiletin (M1), 4′‐demethylnobiletin (M2), and 3′,4′‐didemethylnobiletin (M3) in the colonic mucosa. In contrast, the colonic level of NBT was about 20‐fold lower than the total colonic level of three metabolites. Cell culture studies demonstrated that the colonic metabolites of NBT significantly inhibited the growth of human colon cancer cells, caused cell‐cycle arrest, induced apoptosis, and profoundly modulated signaling proteins related with cell proliferation and cell death. All of these effects were much stronger than those produced by NBT alone. Conclusion Our results demonstrated that oral administration of NBT significantly inhibited colitis‐associated colon carcinogenesis in mice, and this chemopreventive effect was strongly associated with its colonic metabolites.