Abstract 186: Clinically relevant low dose combination of rosuvastatin and difluoromethylornithine provides effective chemopreventive efficacy against AOM-induced colon cancers in F344 rats .
Authors: Janakiram Naveena B. , Mohammed Altaf , Bryant Taylor , Zhang Yuting , Brewer Misty , Duff Ashley , Biddick Laura , Lightfoot Stan , Steele Vernon , Rao Chinthalapally V. 
Published: August 2014

Abstract
Preclinical and clinical studies suggest that statins and polyamine inhibitors suppress growth, invasion and progression of malignant colon tumors. Experiments were designed to evaluate the human clinical relevant doses of Rosuvastatin and Difluromethylornithine (DFMO), individually and in combination, on azoxymethane (AOM)-induced colon adenocarcinomas (AdCa) in male F344 rats. Eight weeks of age, rats (30-36/group) treated with AOM to induce the colonic tumors and nine weeks after the AOM treatment, groups of rats were fed AIN-76A diets containing Rosuvastatin (50 or 100 ppm), DFMO (500 or 1000 ppm), or their low dose combination for an additional 40 weeks. AOM-treated rats fed control diet showed AdCa multiplicity of 3.59 ± 0.48 (Mean ±SEM) and AdCa incidence of 96.6 %. 50 or 100 ppm Rosuvastatin significantly suppressed AdCa multiplicities (29%, p&lt;0.046 and 42%, p&lt;0.007, respectively). 100 ppm Rosuvastatin, but not the lower dose, significantly inhibited colon AdCa incidence (p&lt;0.02) and caused &gt;52% (p&lt;0.003) more inhibition of invasive AdCa multiplicity. As anticipated, DFMO at both doses significantly inhibited AdCa multiplicity (p&lt;0.003 - p&lt;0.0001) and incidence (p&lt;0.05-0.001) as compared to control diet. The combination of low-dose Rosuvastatin plus low dose DFMO suppressed colon AdCa multiplicity by 76% (p&lt;0.0001) as compared to low-dose Rosuvastatin (29%) and low-dose DFMO (46%), suggesting an additive effect. This low dose combination also resulted in delay of colonic AdCa progression, as revealed by the presence of a higher number of adenomas in the treated group as compared to the low adenoma/high AdCa occurrence in the control diet group. DFMO, Rosuvastatin and/or combinations caused significantly decreased expression of cyclin E, cdk2, cav-1, laminin 1β, and mutant p53 proteins, and increased expression of wild type p53, cdc25c and p21 compared to control tumors by Western immunoblotting and Immunohistochemistry. The inflammatory markers IL-6, stat3, and COX-2 and the proliferation markers β-catenin and cyclin D1 also were down-regulated significantly in tumors of rats fed low-dose combinations as compared to low doses of Rosuvastatin or DFMO alone. This first report on combination treatment using clinically relevant doses of statin plus DFMO shows significant suppression of colon AdCa. Further studies are warranted using low-dose combinations of Rosuvastatin and DFMO in individuals at high risk for colon cancer. (Supported by R01-CA-94962 & NCI-CN-N01-53300)
Citation Format: Naveena B. Janakiram, Altaf Mohammed, Taylor Bryant, Yuting Zhang, Misty Brewer, Ashley Duff, Laura Biddick, Stan Lightfoot, Vernon Steele, Chinthalapally V. Rao. Clinically relevant low dose combination of rosuvastatin and difluoromethylornithine provides effective chemopreventive efficacy against AOM-induced colon cancers in F344 rats . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 186. doi:10.1158/1538-7445.AM2013-186