Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats

Abstract

Abstract.Omeprazole is a proton pump inhibitor, a widely used drug to treat ulcers and gastroesophageal refluxdisease. We have evaluated colon cancer chemopreventive properties of omeprazole using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats and analyzed cell growth inhibition and apoptosis induction in human colon cancer cells. Five-week-old male F344 rats were fed a control or experimental diet containing two doses of omeprazole (200 and 400 ppm). After one week, all animals were s.c. injected with AOM (15 mg/kg body weight, once weekly for two weeks). Rats continued on experimental diets for seven more weeks before being sacrificed. Colons were histopathologically evaluated for ACF. Human colon cancer HCT-116 and HCA-7 cells treated with omeprazole were evaluated for different markers associated with proliferation and apoptotic markers using Western blot technique. Rats fed with 200 and 400 ppm of omeprazole significantly suppressed total colonic ACF formation (~30%, P<0.001) and showed significant suppression of multi-crypt foci (~30-50%, P<0.05-0.001). Omeprazole produced significant dose-response effects on inhibition of multi-crypt foci (≥4). Omeprazole treatment in human colon cancer cell lines HCT-116 and HCA-7 cells resulted in induction of p21 waf1/cip1 and decreased the expression of anti-apoptotic proteins Bcl-2, Bcl-X L and survivin in a dose-dependent manner. Anticancer properties observed in colon cancer cell lines suggest that omeprazole may induce key signaling molecules of antiproliferation and inhibition of anti-apoptotic proteins.

Colon cancer-induced interleukin-35 inhibits beta-catenin-mediated pro-oncogenic activity

“…During the past two decades in China, especially in large cities, the incidence rate has been increasing significantly, and colon cancer is higher than the trend of rectal cancer. In the United States, there are about 15 million people who get colon cancer each year, representing 15% of all patients diagnosed with cancer, without gender difference [ 1 ]. Since 1993, Cohen reported that the five-year survival rate of colon cancer was 54%.…”

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

“…The direct effect of this class of drugs on cancer cells were, however, published in several other reports. Omeprazole reportedly prevented azoxymethane-induced colonic aberrant crypt foci development in male F344 rats as well as reducing HCT-116 and HCA-7 colon cancer cell growth [230]. Esomeprazole was found to inhibit MDA-MB 468 triple negative breast cancer cell growth while rabeprazole had growth inhibitory effects on MKN 28 and AGS gastric cancer cell lines [231,232].…”

Effect of Proton Pump Inhibitors on Colorectal Cancer

“…Several reports have shown the anti-tumoral effects of PPIs. PPIs were shown to suppress proliferation of colon cancer cell lines and carcinogenesis in a rat azoxymethane (AOM) model [4]. The long-term use of PPIs was reported not to affect colorectal adenoma development or result in histological changes [5].…”