δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages

Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (-T), beta (-T), gamma (-T), and delta (-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with -T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of -T is weak compared to other tocopherol forms. In the present study, we investigated the effects of -T, -T, and -T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10wk. Dietary supplementation with -T and -T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-B p65 and p-STAT3) in tumors and adjacent tissues. By administering -T at different time periods, we obtained results suggesting that the inhibitory effect of -T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. -T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of -T and -T in a physiologically relevant model of human colon cancer. (c) 2016 Wiley Periodicals, Inc.