Green tea polyphenols inhibit colorectal aberrant crypt foci (ACF) formation and prevent oncogenic changes in dysplastic ACF in azoxymethane-treated F344 rats

Abstract

Green tea and its constituents have shown cancer-preventive activities in many animal models. In order to prepare for a human trial on the inhibition of colon carcinogenesis, we conducted a study with green tea polyphenols as the preventive agent in an azoxymethane (AOM)-induced rat colon cancer model using aberrant crypt foci (ACF) as an end point. F344 rats were given two weekly injections of AOM (15 mg/kg), and then fed a 20% high-fat diet with or without 0.12 or 0.24% Polyphenon E (PPE, a standardized green tea preparation consisting 65% of (-)-epigallocatechin-3-gallate and 22% of other catechins) for 8 weeks. Colorectal ACF were analyzed under a microscope after methylene blue staining. Dietary PPE administration was found to significantly and dose dependently decrease the total number of ACF per rat and the total number of aberrant crypt per rat. Moreover, treatment with 0.24% PPE also significantly decreased the percentage of large ACF (four or more crypts) and the percentage of ACF with high-grade dysplasia in total ACF. The high-grade dysplastic ACF from 0.24% PPE-treated group had increased apoptosis and decreased nuclear expression levels of beta-catenin and cyclin D1. Retinoid X receptor (RXR)alpha expression was reduced in high-grade dysplastic ACF, adenoma and adenocarcinoma during AOM-induced colon carcinogenesis, and the PPE treatment partially prevented the loss of RXRalpha expression in high-grade dysplastic ACF. Taken together, our results strongly suggest the colon cancer-preventive activity of PPE and identified possible molecular markers for future colon cancer prevention studies.