Abstract 808: Chemoprevention of colon cancer by DFMO, sulindac and NO-sulindac administered individually or in combinations in male F344 rats

Abstract

Abstract Different mode of action exerted by low-dose combination of agents represents a practical approach for improving the chemopreventive efficacy and minimizing unwanted toxicities. Recent clinical studies in high-risk sporadic colorectal cancer patients proven that DFMO combined with COX-1/COX-2 inhibitor, sulindac dramatically reduced polyps formation. Present study designed to address whether i) low-dose combinations DFMO and sulindac would provide the efficacy against rat colon adenocarcinomas in rat model representing human sporadic colon cancers; ii) test the advantages of nitric-oxide releasing (NO)-sulindac would provide colon cancer chemopreventive activity alone or combined with DFMO; and iii) understand the molecular changes associated in colon tumor inhibition by these combinations. Seven-week old, male F344 rats (36 rats/group) were fed the control AIN-76A diet and AOM (15 mg/kg b.w., once weekly for 2 weeks, at the age of 8 and 9 weeks) administered by s.c. Eight weeks after the last carcinogen treatment, rats were fed the diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, 200 ppm NO-Sulindac individually or in combinations for 40 weeks. Rats were sacrificed and colon tumors were evaluated by histopathologically and colonic tissues were assayed for expression levels of COX-2, iNOS, p21WAF1/CIP1, apoptotic markers, and cell proliferation (BrdU) and ODC enzymatic activity. Bioassay results suggest that administration of 500 ppm DFMO and 150 ppm sulindac significantly suppressed total adenocarcinoma multiplicity by 50% (p<0.003) and 35.4% (p<0.03), respectively; whereas NO-sulindac had no significant effect on AOM-induced colon cancers. Importantly, combination of DFMO with sulindac or NO-Sulindac significantly suppressed colon adenocarcinoma incidence (42%p<0.0004; 32% p<0.001), and multiplicity (58%, p<0.0001; 52%, p<0.0018). We observed greater inhibitory effects of DFMO (63%), sulindac (52%) alone and more pronounced inhibitory DFMO combined with sulindac (78%) on adenocarcinomas with size of >0.5-mm. Colonic adenocarcinomas harvested from rats fed DFMO, sulindac or combinations showed significant inhibition of COX-2 and iNOS expression and activity compared to control diet fed rat colonic tumors. Also, DFMO and sulindac or combinations showed considerable enhancement of p21WAF1/CIP1, caspase-3 cleavage, down regulation of bcl-xL, bcl-2 and survivin in rat colonic tumors. Rats that were fed with the combination DFMO and sulindac showed reduced tumor cell proliferation (BrdU labeling index by 16-28%, p<0.05-0.01) in colonic tumors. These observations show that combination of low-dose DFMO and sulindac possesses significant colon tumor inhibitory properties; whereas 200 ppm NO-sulindac alone or combined with DFMO had modest colon tumor inhibitory effects. [Supported by NIH, NCI grants NO1-CN-35110 and R01 CA-102942)] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 808. doi:10.1158/1538-7445.AM2011-808