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Inhibition of colon carcinogenesis by 5‐demethylnobiletin in azoxymethane‐treated rats
Author(s) -
Song Mingyue,
Wu Xian,
Wang Minqi,
Xiao Hang
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.753.5
Subject(s) - azoxymethane , apoptosis , carcinogenesis , carcinogen , cell growth , colorectal cancer , blot , immunohistochemistry , cell , cancer research , inflammation , cell cycle , western blot , aberrant crypt foci , pharmacology , chemistry , medicine , cancer , biochemistry , colonic disease , gene
We previously demonstrated that 5‐demethylnobiletin (5DN, a unique citrus flavonoid) had potent anticancer effects in both cell culture and mouse models of colon carcinogenesis. In this study, we determined the inhibitory effects of 5DN on AOM‐induced colon carcinogenesis in F344 rats. After carcinogen administration, F344 male rats were treated with two different doses of 5DN in the diet for 40 weeks. Our results showed that treatment of 5DN showed dose‐dependent inhibition on colon tumor incidence and tumor multiplicity. Immunohistochemical analysis showed that 5DN modulated the expression levels of multiple signaling proteins, indicating increased apoptosis, decreased cell proliferation and decreased inflammation in the colonic mucosa. These results were further confirmed by Western blotting assay. HPLC analysis showed that oral administration of 5DN resulted in high levels of 5DN and its metabolites i.e. 5,3'‐didemethylnobiletin (M1), 5,4'‐didemethylnobiletin, and 5,3'(M2), 4'‐tridemethylnobiletin (M3) in the colonic tissues of rats. Cell culture study showed that these metabolites, especially M1 had much stronger inhibitory effects on human colon cancer cells in comparison to 5DN. Flowcytometry analysis indicated that 5DN metabolites induced extensive cell cycle arrest and apoptosis in colon cancer cells. In conclusion, our results demonstrated that dietary treatment of 5DN significantly inhibited colon carcinogenesis in rats and this effect can be partially attributed to the colonic metabolites of 5DN