Combination of Atorvastatin with Sulindac or Naproxen Profoundly Inhibits Colonic Adenocarcinomas by Suppressing the p65/β-Catenin/Cyclin D1 Signaling Pathway in Rats

Abstract

Evidence supports the protective role of non-steroidal anti-inflammatory drugs (NSAIDs) and statins against colon cancer. Experiments were designed to evaluate the efficacies atorvastatin and NSAIDs administered individually and in combination against colon tumor formation. F344 rats were fed AIN-76A diet and colon tumors were induced with azoxymethane (AOM). One week after the second AOM-treatment groups of rats were fed diets containing atorvastatin (200 ppm), sulindac (100 ppm) or naproxen (150 ppm), or their combinations with low-dose atorvastatin (100 ppm) for 45 weeks. Administration of atorvastatin at 200 ppm significantly suppressed both adenocarcinoma incidence (52% reduction, p=0.005) and multiplicity (58% reduction, p=0.008). Most importantly, colon tumor multiplicities were profoundly decreased (80–85% reduction, p<0.0001) when given low-dose atorvastatin with either sulindac or naproxen. Also, a significant inhibition of colon tumor incidence was observed when given a low-dose atorvastatin with either sulindac (p=0.001) or naproxen (p =0.0005). Proliferation markers, proliferating cell nuclear antigen, cyclin D1 and β-catenin in tumors of rats exposed to sulindac, naproxen, atorvastatin, and/or combinations showed a significant suppression. Importantly, colon adenocarcinomas from atorvastatin and NSAIDs fed animals showed reduced key inflammatory markers, inducible nitric oxide synthase and cyclooxygenase-2, phospho-p65, as well as inflammatory cytokines, TNF-α, IL-1β, and IL-4. 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 adenocarcinoma incidence and multiplicity. Our results suggest that low-dose atorvastatin with sulindac or naproxen might potentially be useful combinations for colon cancer prevention in humans.

The Role of Inflammation in Colon Cancer

“…This study suggested that its inhibitory function may be due to its modulatory effects on AA metabolism. In another study by Suh et al (2011), the NSAIDs sulindac and naproxen, individually and in combination with atorvastatin, caused significant reduction in AOM-induced colon tumors in F344 rats. The NSAID-fed animals showed reduction in inflammatory markers iNOS and COX-2 as well as in phospho-p65 and in the pro-inflammatory cytokines TNF-α, IL-1β, and interleukin 4 (IL-4).…”

The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer

“…To date, no clinical evidence exists to support the role of statins in influencing the local inflammatory response in CRC, although pre-clinical data suggests a direct inhibitory effect on NF-ƙB activation, with subsequent down-regulation of COX-2 and pro-inflammatory cytokine expression (92)(93)(94). A cohort study of patients undergoing radical prostatectomy found that statin use was associated with a reduced tumour inflammatory infiltrate (95); in contrast to CRC, however, a minimal local inflammatory response is associated with reduced recurrence and improved survival.…”

Inflammatory Dysregulation and Cancer: From Molecular Mechanisms to Therapeutic Opportunities

“…Statins may also have a role to play in downregulating infl ammation in attempts to prevent cancer. Consistent downregulation of pro-infl ammatory cytokines in cardiovascular trials has been demonstrated (Jain and Ridker 2005 ), this is supported by preclinical data that confi rms inhibition of NF-κB signalling and pro-infl ammatory cytokines in cancer models (Lee et al 2007 ;Suh et al 2011 ). The infl uence of statins on infl ammation across all cancers is inconsistent, with one study showing no benefi t in colorectal cancer development (Coogan et al 2007 ).…”