Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

Abstract

Colitis-associated cancers arise in the setting of chronic inflammation wherein an "inflammationdysplasia-carcinoma" sequence prevails. Based on our previous findings in which the proton pump inhibitor could impose significant levels of anti-inflammatory, antiangiogenic, and selective apoptosis induction beyond gastric acid suppression, we investigated whether omeprazole could prevent the development of colitis-associated cancer in a mouse model induced by repeated bouts of colitis. Omeprazole, 10 mg/kg, was given i.p. all through the experimental periods for colitis-associated carcinogenesis. Molecular changes regarding inflammation and carcinogenesis were compared between control groups and colitis-associated cancer groups treated with omeprazole in addition to chemopreventive outcome. Nine of 12 (75.0%) mice in the control group developed multiple colorectal tumors, whereas tumors were noted in only 3 of 12 (25.0%) mice treated with daily injections of omeprazole. The cancer-preventive results of omeprazole treatment was based on significant decreases in the levels of nitric oxide, thiobarbituric acid-reactive substance, and interleukin-6 accompanied with attenuated expressions of tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2. The expressions of matrix metalloproteinase (MMP)-9, MMP-11, and MT1-MMMP were significantly decreased in mice treated with omeprazole in accordance with significant decreases in the number of β-catenin-accumulated crypts. A significant induction of apoptosis was observed in tumor tissue treated with omeprazole. Omeprazole could block the trophic effect of gastrin in colon epithelial cells. The significant anti-inflammatory, antioxidative, and antimutagenic activities of omeprazole played a cancer-preventive role against colitisinduced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression. Cancer Prev Res; 3(8); 963-74. ©2010 AACR.

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

“…Omeprazole treatment decreased the levels of the anti-apoptotic proteins Bcl-2 and Bcl-X L in a dose-dependent manner. In addition to Bcl-2 and Bcl-X L , we tested caspase-3 cleavage but did not find any changes in caspase-3 in contrast to earlier findings reported by Scaringi in Jurkat cells (32) and also by Kim et al (11) in animal models. In general, Bcl-2 and Bcl-X L appear to control cell survival by inhibiting the intrinsic apoptotic pathway, which is regulated by a mitochondrial pathway, cytochrome C release, and mediated by caspase-9, caspase-3 cleavage (30).…”

“…Previous studies have demonstrated anti-inflammatory and cytoprotective actions in gastric mucosal and endothelial cells (6,8,9). Furthermore, in vivo studies support the anticancer properties of omeprazole (11,12). With regard to colon carcinogenesis, Penman et al (10) reported chemopreventive properties of omeprazole treatment reduced colon carcinogenesis in Sprague-Dawley rats.…”

“…With regard to colon carcinogenesis, Penman et al (10) reported chemopreventive properties of omeprazole treatment reduced colon carcinogenesis in Sprague-Dawley rats. Kim et al (11) reported anti-inflammatory, anti-oxidative, and anti-mutagenic activities of omeprazole in colitis-associated carcinogenesis in mouse models. Omeprazole-induced hyper-gastrinaemia has consistently failed to increase tumor incidence in carcinogen-induced colorectal malignancy in rats (10,12,13).…”

Current overview of colitis-associated colorectal cancer

“…Omeprazol is believed to reverse the progression of inflammation-initiated or promoted carcinogenesis through antioxidative, antiinflammatory, and antimutagenic effect independent of action on gastric acid [56].…”

Prevention of Colitis-Associated Colorectal Cancer with 8-Hydroxydeoxyguanosine

“…Isolated tissues for histologic examination were spread onto a plastic sheet, fixed in 3.7% formalin for 5 hours, and prepared for paraffin tissue slides (25). The paraffin sections were stained with hematoxylin and eosin (H&E) or saved for immunohistochemical staining.…”