Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice

Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (alpha-T), beta-T, gamma-T and delta-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of alpha-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than alpha-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a gamma-T-rich mixture of tocopherols (gamma-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified delta-T, gamma-T or alpha-T (0.2% in diet) showed that delta-T was more effective than gamma-T or alpha-T in preventing mPIN formations and p-AKT elevation. These results indicate that gamma-TmT and delta-T could be effective preventive agents of prostate cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.