Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression.
Colitis-associated cancers arise in the setting of chronic inflammation wherein an "inflammation-dysplasia-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-alpha, 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 beta-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 colitis-induced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression.
Kim
Yoon Jae
YJ
Department of Gastroenterology, Gachon University of Medicine and Science, Incheon, Korea.
Lee
Jeong Sang
JS
Hong
Kyung Sook
KS
Chung
Jun Won
JW
Kim
Ju Hyun
JH
Hahm
Ki Baik
KB
D000818:Animals; D002277:Carcinoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D003092:Colitis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009853:Omeprazole / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*
D054328:Proton Pump Inhibitors; D009853:Omeprazole