Suppression of azoxymethane‐induced colonic preneoplastic lesions in rats by 1‐methyltryptophan, an inhibitor of indoleamine 2,3‐dioxygenase

Abstract

The escape of preneoplastic cells from the immune system, which is caused by immune tolerance, occurs during the development of several types of tumors. Indoleamine 2,3-dioxygenase (IDO) plays a critical role in the induction of immune tolerance. In the present study we investigated the effects of 1-methyltryptophan (1-MT), an IDO inhibitor, and (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, on the development of azoxymethane (AOM)-induced colonic preneoplastic lesions by focusing on the inhibition of IDO. To induce colonic premalignant lesions, male F344 rats were injected with AOM (20 mg/kg body weight, s.c.) once a week for 2 weeks. They also received 0.2% 1-MT or 0.1% EGCG in their drinking water for 4 weeks, starting 1 week before the first dose of AOM. Both 1-MT and EGCG significantly decreased the total number of aberrant crypt foci and β-catenin-accumulated crypts, which overexpressed IDO protein. Treatment with EGCG decreased IDO mRNA expression in both the colonic epithelium and stroma of rats induced by AOM. The AOM-induced increase in cyclooxygenase-2 mRNA expression in the colonic stroma was significantly decreased by EGCG. Furthermore, AOM-induced increases in IDO activity in the serum and stroma were significantly inhibited by 1-MT and EGCG. Inhibition of IDO activity by 1-MT and EGCG was also observed in cell-free assays. These findings suggest that upregulation of IDO activity is observed in the early stages of colon carcinogenesis and that the use of IDO inhibitors, such as 1-MT and EGCG, which suppress the occurrence of colonic preneoplastic lesions, could be a novel strategy for the chemoprevention of colon cancer.