Abstract A15: Chemopreventive efficacy of Phospho-Ibuprofen, Rosuvastatin and their combination on AOM-induced colon adenocarcinoma formation in F344 rats

Abstract

Abstract Phospho-Ibuprofen (P-I) is a derivative of ibuprofen designed to reduce the traditional toxicities of non-steroidal anti-inflammatory drugs (NSAIDs). P-I is studied for its anti-inflammatory and cancer properties in arthritis, breast cancer models and showed better gastrointestinal safety compared to NSAIDs. Statins has been effective for cholesterol lowering and protecting cardiovascular diseases in addition to its antineoplastic effects in preclinical and clinical observations. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs in combination is to produce synergy without any unwanted side effects. Hence, experiments were designed to evaluate the chemopreventive efficacies of P-I and Rosuvastatin, which were administered individually and in combination on azoxymethane (AOM)-induced colon cancer formation in F344 rats. Male F344 rats (~30-45 animals/group) were fed AIN-76A diet and colon tumors were induced with two weekly doses of AOM (15 mg/kg body wt). Eight weeks after the AOM-treatment, groups of rats were fed AIN-76A diets containing ibuprofen (200 ppm), P-I (360 and 720 ppm), Rosuvastatin (50 and 100 ppm), or their low dose combinations for 40 weeks. Colonic tumors were evaluated histopathologically as invasive and noninvasive adenocarcinomas (AdCa) and modulating effects of P-I, and Rosuvastatin and combinations were studied on markers of colon tumor cell proliferation and apoptosis. Results: Administration of P-I at 720 ppm significantly suppressed AOM-induced colon non-invasive and invasive AdCa formation (multiplicity (Mean±SEM): Non-invasive AdCa: Untreated, 1.37±0.22; P-I treated, 0.70±0.14 (p<0.006); Invasive AdCa, Untreated, 2.22±0.35; P-I treated, 1.27±0.20 (p<0.01). Rosuvastatin showed significant inhibition of noninvasive AdCa [50 ppm 1.43±0.21 (p<0.03); 100 ppm 1.06±0.18 (p<0.003)]. Importantly, low dose combination of 360 ppm P-I + 50 ppm Rosuvastatin showed significant synergistic/additive effect on the inhibition of colon non-invasive (44.5%, p<0.016) and invasive AdCa (58.2%, p<0.0002) multiplicity, suggesting a more pronounced effect on invasive AdCa. Whereas administration of 200 ppm Ibuprofen equalant to 360 ppm P-I failed to show any significant protective (p>0.05) effect on AOM-induced AdCa multiplicity or incidence. Proliferation markers, proliferating cell nuclear antigen (PCNA), Cdk2, Cdc25C and Cav1, in tumors of rats exposed to P-I, Rosuvastatin and/or combinations were significantly suppressed. Also, colonic tumors from rats fed combination diet showed significant suppression of Erk and pErk protein expression as compared to colon tumors from rats fed the control diet. This is the first report on the combination using low-dose P-I and Rosuvastatin, which significantly suppressed the colon adenocarcinomas. Our results suggest that low-dose P-I with Rosuvastatin might potentially be a useful combination for colon cancer prevention/treatment in high risk individuals. (Supported by NCI-CN-N01-53300). Citation Format: Naveena B. Janakiram, Altaf Mohammed, Yuting Zhang, Misty Brewer, Taylor Bryant, Laura Biddick, Stan Lightfoot, Vernon E. Steele, Chinthalapally V. Rao. Chemopreventive efficacy of Phospho-Ibuprofen, Rosuvastatin and their combination on AOM-induced colon adenocarcinoma formation in F344 rats. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A15.