Abstract 202: Tocopherols inhibit the dietary carcinogen PhIP-induced prostate carcinogenesis in a CYP1A-humanized mouse model.

Abstract

Abstract γ-TmT, a tocopherol mixture that is rich in γ-tocopherol (γ-T), containing 56.8% γ-T, 24.3% δ-T, 13.0% α-T and 1.5% β-T, has been shown to inhibit colon, lung, mammary and prostate tumorigenesis in our previous studies, whereas α-T was ineffective. The present work investigated the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced prostate carcinogenesis in CYP1A-humanized (hCYP1A) mice by γ-TmT. Male hCYP1A mice, maintained on the AIN93M diet or the same diet supplemented with 0.3% γ-TmT, were treated with a dose of PhIP (200 mg/kg, i.g.). At week 40 after PhIP treatment, all mice developed high-grade prostate intraepithelial neoplasia (hgPIN) in the dorso-lateral glands. The hgPIN was associated with elevated levels of 8-oxo-deoxyguanosine (8-oxo-dG), DNMT1, COX-2 and p-AKT, as well as with loss of expression of the tumor suppressor PTEN, E-cadherin, GSTP1 and Nrf2 in the dorso-lateral glands. In the γ-TmT group, the number of glands with hgPIN (per 100 glands) was significantly lower than the control group (14.6 ± 4.87 vs. 34.81 ± 3.87, p < 0.01). The γ-TmT treatment also prevented the elevation of 8-oxo-dG, COX-2 and p-AKT and the loss of PTEN and Nrf2. The γ-TmT treatment significantly increased the plasma levels of γ-T and δ-T (to 1.7 and 0.8 μM, respectively) as well as their side-chain degradation metabolites, carboxyethyl hydroxychromans and carboxymethylbutyl hydroxychromans (to 2.6-4.0 μM, higher than their parent tocopherols). In a short-term experiment, PhIP-treatment elevated levels of 8-oxo-dG, γH2AX and DNMT1, and caused gene expression changes in several p53-associated genes, including p53bp1, p21WAF1/CIP1, cyclin D1, Bax, Igf1 and cyclinG1 at 1 and/or 3 days after PhIP treatment. Dietary γ-TmT treatment partially prevented the elevation of 8-oxo-dG, γH2AX and DNMT1. This action may contribute to the prostate cancer preventive effect of tocopherols. The presently observed inhibitory activities of γ-TmT against prostate carcinogenesis are hypothesized to be due to the decrease of oxidative stress and inhibition of AKT phosphorylation by γ- and δ-tocopherols, and this hypothesis remains to be tested further (supported by NIH grants CA159361 & CA133021). Citation Format: Guangxun Li, Hong Wang, Anna B. Liu, Jayson X. Chen, Mao-Jung Lee, Chung S. Yang. Tocopherols inhibit the dietary carcinogen PhIP-induced prostate carcinogenesis in a CYP1A-humanized mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 202. doi:10.1158/1538-7445.AM2013-202