Abstract A40: Inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced prostate and colon carcinogenesis in hCYP1A mice by tocopherols

Abstract

Abstract We have previously demonstrated that γ-tocopherol (γ-T), δ-T and γ-TmT (a tocopherol mixture containing 56.8% γ-T, 24.3% δ-T, 13.0% α-T and 1.5% β-T) inhibited colon, lung, mammary and prostate tumorigenesis; δ-T was more active than γ-T, whereas α-T was ineffective. The present work extends the research to studies in the PhIP (a dietary carcinogen)-induced prostate and colon carcinogenesis in hCYP1A (CYP1A-humanized) mice. Both models are newly established in our lab. 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 8-oxo-deoxyguanosine (8-oxo-dG) and DNA methyltransferase 1 (DNMT1) as well as with loss of expression of the tumor suppressor PTEN and E-cadherin. The number of glands with hgPIN (per 100 glands) in the γ-TmT group was significantly lower than the control group (14.6 ± 4.87 vs. 34.81 ± 3.87, p < 0.01). Oxidative stress and other molecular markers were also decreased in the γ-TmT group. In a short-term experiment, dietary γ-TmT treatment partially prevented the elevation of 8-oxo-dG, γH2AX and DNMT1 in the dorso-lateral glands analyzed at 3 days after PhIP treatment. This action may contribute to the prostate cancer preventive effect of tocopherols. For the induction of colon cancer, female hCYP1A mice were administered a dose of PhIP (200 mg/kg, i.p.) followed by treatment with dextran sulfate sodium (1.5% in drinking water) for a week. Colon carcinoma developed in 6-8 weeks after PhIP treatment, and 92% of the tumors had β-catenin mutations at codons 32 and 34. Dietary treatment with 0.3% γ-TmT, starting 1 week before PhIP administration, decreased the colon tumor multiplicity (1.6 ± 0.41 vs. 4.3 ± 1.16 of the control group, in number of tumors/mouse, p < 0.05). Similar results were also observed in 2 other sets of experiments. These studies demonstrate the cancer prevention activity of γ-TmT in PhIP-induced models for prostate and colon cancers. Since γ-TmT is rich in γ-T and δ-T, its cancer prevent activities are likely to be due to γ-T and δ-T. The present results further support our proposal that γ-T, δ-T and γ-TmT are potential cancer preventive agents (supported by NIH grants CA120915 & CA133021 and the John L. Colaizzi Chair Endowment Fund). Citation Format: Guangxun Li, Yu-Kuo Chen, Hong Wang, Anna B. Liu, Chen X. Chen, Xiangyi Guo, Xi Zheng, Nanjoo Suh, Chung S. Yang. Inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced prostate and colon carcinogenesis in hCYP1A mice by tocopherols. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A40. Note: This abstract was not presented at the conference.