Colorectal cancer (CRC) causes over 53,000 deaths annually in the United States. Its rising incidences worldwide and particularly in young adults is a major concern. Here, we evaluated the efficacy of omeprazole (OME) that is clinically approved for treating acid-reflux, to enable its repurposing for CRC prevention. In the azoxymethane (AOM)-induced rat CRC model, dietary OME (250 and 500 ppm) was administered at early adenoma stage (8 weeks after AOM) to assess the progression of early lesions to adenocarcinoma. Administration of OME at 250 ppm or 500 ppm doses led to suppression of total colon adenocarcinoma incidence by 15.7% and 32% (p<0.01), respectively. Importantly, invasive carcinoma incidence was reduced by 59% (p<0.0005) and 90% (p<0.0001) in OME administered rats in a dose-dependent manner. There was also a strong and dose-dependent inhibition in the adenocarcinoma multiplicity in rats exposed to OME. Administration of 250 and 500 ppm OME inhibited total colon adenocarcinoma multiplicity by ~49% and ~65% (p<0.0001), respectively. While non-invasive adenocarcinomas multiplicity was suppressed by ~34% to ~48% (p<0.02), the invasive carcinomas multiplicity was reduced by ~74% to ~94% (p<0.0001) in OME exposed rats in comparison to the untreated rats. Biomarker analysis results showed a decrease in cell proliferation and anti-apoptotic/pro-survival proteins with an increase in apoptosis. Transcriptome analysis of treated tumors revealed a significant increase in adenocarcinoma inhibitory genes (Olmf4; Spink4) expression and down regulation of progression promoting genes (SerpinA1, MMP21, IL6). In summary, OME showed significant protection against the progression of adenoma to adenocarcinoma.
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