Abstract 1633: Chemopreventive efficacy of raloxifene, bexarotene and their combination on the progression of AOM-induced colon adenomas to adenocarcinomas in F344 rats
Authors: Naveena B. Janakiram, Altaf Mohammed, Yuting Zhang, Misty Brewer, Stan Lightfoot, Vernon E. Steele, Chinthalapally V. Rao
Journal: Cancer Research (2012)

Abstract Estrogen Receptor (ER)-α signaling is positively associated with colon carcinogenesis as evidenced from pre-clinical and clinical trials. Whereas, down regulation or loss of function of retinoid X receptors (RXR)-α is identified in colon tumors. Both of these receptors play a vital role in growth, development and apoptosis of cells. Bexarotene, a selective agonist for RXR-agonist, is well studied for small cell lung carcinoma and breast cancer. Among the SERMs, raloxifene is an estrogen antagonist in the colon, which has been protective against the colonic lesion development. Hence, experiments were designed to evaluate the chemopreventive efficacies of raloxifene and bexarotene, which were administered individually and in combination during promotion and progression stages of colon tumor formation in F344 rats. Male F344 rats (36-45 animals/group) were fed AIN-76A diet and colon tumors were induced with azoxymethane (AOM; 1.5m/kg body wt). Nine weeks after the AOM-treatment, groups of rats were fed diets containing either raloxifene (1.5 and 3 ppm), bexarotene (50 and 100 ppm), or their low dose combinations for 40 weeks. We have evaluated colonic tumors histopathologically. Also, we have analyzed modulating effects of raloxifene, and bexarotene and combinations of these agents on the markers of colon tumor cell proliferation and apoptosis. Administration of raloxifene at both the doses significantly suppressed (p&amp;lt;0.001 −0.0001) colon adenocarcinoma formation (multiplicity: Control, 4.62±0.27 Mean±SE; 1.5 ppm raloxifene, 3.28±0.31; 3 ppm raloxifene, 2.96±0.30). Bexarotene also showed significant suppression of colon adenocarcinoma formation with multiplicity of 3.14±0.36 (p&amp;lt;0.001) and 2.9±0.28 (p&amp;lt;0.0001) for 50 ppm and 100 ppm bexarotene, respectively. Importantly, low dose combination of 1.5 ppm Raloxifene + 50 ppm bexarotene showed significant synergistic and/or additive effect on the inhibition of colon adenocarcinoma multiplicity (48%, p&amp;lt;0.0001) when compared to control diet fed rats. Immunohistochemistry for proliferation markers, proliferating cell nuclear antigen, cyclin D1 and β-catenin, in tumors of rats exposed to raloxifene, bexarotene and/or combinations showed a significant suppression. Also, colonic tumors from rats fed combination diet showed significant increased apoptotic cells (3-fold) and p21 expression (3.8-fold) compared to colon tumors from rats fed control diet. This is the first report on the combination treatment using low-dose raloxifene and bexarotene, which significantly suppressed the progression of colonic precursor lesions to adenocarcinomas. Our results suggest that low-dose raloxifene with bexarotene might potentially be a useful combination for colon cancer prevention/treatment in high risk individuals. (Supported by NCI-CN-N01-53300) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1633. doi:1538-7445.AM2012-1633