Abstract A141: Chemopreventive properties of omeprazole against azoxymethane-induced colonic aberrant crypt foci formation in fats

Abstract

Abstract Omeprazole is a proton-pump inhibitor which is widely used to treat ulcers and gastroesophageal reflux diseases (GERD). Previous studies show that omeprazole exhibits possible anti-tumorigenic properties in preclinical models of colon cancer. However, no systematic studies were carried to establish the potential anti-carcinogenic potential of omeprazole using established animal models of colon cancer. In the present study, omeprazole was evaluated for its colon cancer chemopreventive properties using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a efficacy endpoint in F344 rats. In addition, we analyzed the growth inhibitory effects and induction of apoptosis in human colon cancer HCA-7 cells. We also studied its possible anti-inflammatory properties in Raw 264.7 macrophage cell line. Prior to efficacy studies we evaluated the maximum tolerated dose (MTD) of omeprazole. For MTD assay, seven week-old rats were fed either control AIN-76 diet, diets containing 5 different dose levels of omeprazole (100, 200, 400, 600 and 800 ppm) for six weeks. Based on body weight gain and toxicity symptoms, the MTD of Omeprazole is found to be ∼600 ppm. To evaluate the inhibitory properties of omeprazole on colonic ACF, seven-week-old male F344 rats were fed experimental diets containing 0, 200, and 400 ppm of omeprazole. One week later, rats received s.c. injections of azoxymethane (AOM) (15 mg/kg body wt., once weekly for two weeks) or equal volume of normal saline (vehicle). Rats were continued on experimental diets for seven weeks before being sacrificed. Colons were evaluated histopathologically for ACF and immunohistochemistry for PCNA marker to assess the crypt cell proliferation. Administration of omeprazole at 400 ppm significantly suppressed total colonic ACF formation (∼30%, p<0.001) when compared to the control diet group. Rats fed with 200 ppm and 400 ppm of Omeprazole showed significantly lower numbers (∼30–50%, p<0.05–0.001) of multi-crypt foci (≥4 or more). Overall, omeprazole produced significant dose-response effect in preventing colonic ACF formation. In in vitro assays, Omeprazole inhibited phorbol-12-myristate 13-acetate -induced iNOS expression in macrophages in a dose dependent manner. Furthermore, omeprazole induced apoptosis by suppressing survivin in HCA-7 colon cancer cells. The results from this study provides evidence for the first time that omeprazole, a proton-pump inhibitor may be used as a chemopreventive agent against colon carcinogenesis. (Supported by NOI-N01-CN-53300). Citation Information: Cancer Prev Res 2010;3(1 Suppl):A141.