EGCG suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice

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Epidemiological studies suggest that obesity and diabetes mellitus may be risk factors for colon cancer. We previously reported that development of azoxymethane (AOM)-induced dysplastic and neoplastic lesions, i.e., premalignant lesions, of the colon is enhanced in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus due to a mutation of leptin receptor (Hirose, Y., et al. Carcinogenesis 25, 2004). One of the underlying mechanisms leading to the development of colonic premalignant lesions in this mouse model is the activation of the IGF/IGF-1R axis in the colonic mucosa. EGCG, the major biologically active component of green tea, appears to have both antiobesity and antidiabetic effects. EGCG also inhibits the activation of the IGF-1R in human colon cancer cells (Shimizu, M., et al. Biochem Biophys Res Commun 334, 2005). Therefore, in this study we examined the effects of EGCG on the development of colonic premalignant lesions in db/db mice initiated with AOM. Male db/db mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At week 12, we found that drinking with EGCG caused a significant decrease in the number of aberrant crypt foci and β-catenin accumulated crypts in these mice, both of which are premalignat lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the phosphorylated (i.e., activated) form of IGF-1R protein and EGCG in drinking water thus caused a marked decrease in the expression of this protein. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3, while conversely decreasing the serum levels of triglyceride, total cholesterol, insulin, and leptin. These findings suggest that EGCG can overcome the activation of the IGF/IGF-1R axis, thereby inhibiting the development of colonic premalignat lesions in obesity associated colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. Our results provide further evidence that EGCG may be therefore useful in the chemoprevention or treatment of obesity-related colorectal cancer.