Colitis-associated cancer (CAC) is the ultimate consequence of persistent colitis, based on mechanism of prevailing \#8220;dysplasia-carcinoma sequence\#8221; in affected colon. Based on our preliminary findings that proton pump inhibitor (PPI) could impose overt anti-inflammatory, anti-angiogenic actions (Gut 2006; 55:26-33) and induce selective apoptosis of cancer cells (Clin Cancer Res 2004; 15:8687-8696) beyond acid suppression, we investigated whether omeprazole (OMP), one of PPIs, can prevent the CAC development, established only with repeated bouts of colitis in SD rats. OMP (10\#956;g/kg, daily intraperitoneal injection) was given all through the experimental periods, 225 days. Molecular changes comprising of inflammatory cytokines, MMP expressions and activities, \#946;-catenin accumulated aberrant crypts (BCAC), and TNF-\#945; levels were compared between colitis cancer group and colitis cancer group treated with OMP. Similar to CAC development noted in our previous report [tumor incidence was 18/24 (75%), Proteomics 2006; 6:1158-1165], multiple colorectal tumors developed in 9 out of 12 mice (75%). However, only 3 out of 12 mice treated with daily injection of OMP developed CAC (25%). This significant reduction in tumor development after OMP treatment was accompanied with significant decreases in serum NO levels, serum and tissue levels of TNF-\#945;, mucosal levels of iNOS and COX-2. The expressions and activities of MMP-3, MMP-9, and MMP-11 were significantly implicated in our CAC models, but of which levels were significantly decreased in mice treated with OMP. The numbers of BCAC were significantly decreased in OMP treated group with marked attenuation of nuclear translocation of \#946;-catenin in OMP treated mice group. Since PPI treatment could be associated with hypergastrinemia and hypergastrinemia could influence proliferative effect on colon epithelium, we performed another study to trace the influence of gastrin treatment after PPI. OMP could abolish the trophic influence of gastrin in colon cells. Another supportive data for the rationale of PPI trial in inflammatory bowel disease was drawn that PPI could induced significant levels of HO-1 through nrf-2 transcription, exerting anti-inflammatory actions. In conclusion, significant anti-inflammatory and anti-mutagenic activities of PPI enhance the anticipation of beneficial role of PPI in the treatment of IBD, unexpected bystander effect of PPI.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2970.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009