Abstract A53: Chemoprevention of colon cancer by PBIT, an iNOS-selective inhibitor, administered alone or in combination with low-doses of celecoxib, a COX-2 selective inhibitor

Abstract

Abstract Clinical and preclinical studies suggest that NSAIDs and cyclooxygenase (COX)-2 inhibitors such as celecoxib, reduce the risk of colorectal cancer. However high doses of NSAIDs causes gastrointestinal toxicity and increased cardiovascular risk. Inducible nitric oxide synthase (iNOS), like COX-2, is overexpressed in colon tumors. Interestingly, nitric oxide stimulates COX-2 activity and contributes to the tumor growth. The present study examines the effects of S,S′-1,4-phenylenebis(1,2-ethanediyl)bisisothiourea (PBIT), an iNOS-selective inhibitor on 1) azoxymethane (AOM)-induced colon adenocarcinomas in F344 rats 2) evaluates the combined effects of a low-dose PBIT and celecoxib on chemopreventive efficacy in rats. Seven-week old male F344 rats (36/group) were fed control AIN-76A diet and one week later, AOM was administered s.c to induce colonic tumors. Four-weeks after the AOM treatment, groups of rats were fed experimental diets containing either 0, 50, 100 ppm of PBIT or 250 and 500 ppm of celecoxib or a combination of 50 ppm PBIT plus 250 ppm celecoxib. Forty-eight weeks after AOM treatment, rats were killed and the intestinal tumors were evaluated. Multiple samples of colonic tumors from each group were assayed for expression and activity of iNOS, COX-2 and markers of apoptosis and cell proliferation. We found that 50 and 100 ppm PBIT in diet suppressed colon adenocarcinoma incidence by 34.6% (p<0.01) and 43% (p<0.002), respectively. Similarly, dietary PBIT suppressed adenocarcinoma multiplicity by 40% (p<0.05, 50 ppm) and 60% (p<0.006, 100 ppm). Celecoxib at both 250 and 500 ppm significantly suppressed colon adenocarcinoma incidence (55–77%, p<0.002-0.0001) and multiplicity (66–82%, p<0.002 - 0.0002). A low-dose combination of 50 ppm PBIT and 250 ppm celecoxib significanlty suppressed colon adenocarcinoma incidence by 70% and multiplicity by 83% (p<0.0001). Interestingly, a combination of low-dose PBIT and celecoxib produced either equal or increased inhibitory effect when compared with high dose PBIT or celecoxib alone. Rats fed PBIT and/or a combination of PBIT plus celecoxib showed considerable suppression of iNOS (38–59%, p<0.01-0.0001 and COX-2 (44–67%, p<0.0001) activities and increased p21WAF1/CIP expression in colonic tumors. Administration of 100 ppm PBIT, 250 ppm or 500 ppm celecoxib and a combination of 50 ppm PBIT plus 250 ppm celecoxib suppressed tumor cell proliferation (BrdU index by 22–53%, p<0.05-0.0001) when compared with colon tumors from the control group. Significant levels of apoptotic cells were observed in the adenocarcinomas of celecoxib fed rats and also in rats fed with a combination of low-dose PBIT and celecoxib. These observations demonstrate, for the first time, that the iNOS-selective inhibitor possesses dose-dependent chemopreventive activity in well-established models of colon cancer and a combination of low-dose PBIT and celecoxib significantly enhanced colon cancer chemopreventive efficacy. [Supported by NIH grants R01-CA-102947] Citation Information: Cancer Prev Res 2010;3(1 Suppl):A53.