Abstract 833: Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/beta-catenin/cyclin D1 signaling pathway in rats

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Colorectal cancer is the third leading cause of death from cancer worldwide. Evidence support the protective role of non-steroidal anti-inflammatory drugs (NSAIDs) and statins. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon adenocarcinoma (AdCa) formation. Also, we evaluated colonic AdCa inhibitory action of atorvastatin and NSAIDs in regulating the expression of key protein markers and cytokines. F344 rats were fed AIN-76A diet and colon AdCa were induced with azoxymethane (AOM). One week after AOM-treatment (adenoma-stage) groups of rats were fed AIN-76A diet containing atorvastatin (200 ppm), sulindac (100 ppm) or naproxen (150 ppm), or their combinations with atorvastatin (100 ppm) for 45 weeks. We found that rats fed experimental diets were comparable body weights and without any observable toxicity. Most of AOM-treated control-diet fed rats developed AdCa (74.2% incidence) at 45 weeks. Administration of sulindac and naproxen individually had modest inhibitory (∼25% incidence and ∼33% multiplicity) effect on colon AdCa. However, 200 ppm atorvastatin significantly suppressed both AdCa incidence (>52%, p<0.005) and multiplicity (59%, p<0.003). Importantly, colon AdCa incidence was significantly decreased when rats were given low-dose atorvastatin with either sulindac (p<0.001) or naproxen (p <0.0005). Also, colon AdCa multiplicities were profoundly reduced (80-85%, p<0.0001) when rats were given low-dose atorvastatin with either sulindac or naproxen. The staining of proliferation markers, PCNA, cyclin D1 and beta-catenin indicated that the tumors from the control group had the strong positive staining in the cells, whereas sulindac, naproxen, atorvastatin, and/or combinations had much weaker positive staining. Importantly, colon AdCa from atorvastatin and NSAIDs fed animals showed reduced expression of key inflammatory markers as well as nuclear staining for phospho-p65, a key molecule in the NF-kB pathway. In addition, atorvastatin and NSAIDs combination decreased mucosal and colonic tumor levels of the pro-inflammatory cytokines, TNF- alpha, IL-1 beta, IL-4 and IL-10. Overall, this is the first report on the combination treatment using low-dose atorvastatin with either low dose sulindac or naproxen, which greatly suppress the colon AdCa incidence and multiplicity. Also, our results suggest that decreased inflammatory cytokines and signaling molecules, particularly inhibition of nuclear p65, beta-catenin and cyclin D1 are responsible for suppression of colonic AdCa. In summary, low-dose atorvastatin with sulindac or naproxen might potential useful combinations for colon cancer prevention in humans. (Supported by NCI-N01-CN-53300 and R01-CA94962) 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 833. doi:10.1158/1538-7445.AM2011-833