Abstract 4392: Targeting HADC-2: Chemopreventive effect of OSU-HDAC42 on rat colon carcinogenesis and APCmin/+ Mice intestinal tumorigenesis.

Abstract

Abstract Epigenetic modulators particularly histone deacetylases (HDACs) are valid targets cancer for prevention and Therapy. Recent studies from our laboratory and others suggest that HDAC-2 over-expression is associated with colon tumor progression and potential target for colon cancer prevention. The present study explored the chemopreventive effects of novel HDAC-2 inhibitor, OSU-HDAC42, in a mouse model of familial adenomatous polyposis (FAP). We used a rat colon carcinogenesis model assay, inhibition of aberrant crypt foci (ACF) development, as measure of the dose-response and chemopreventive effects. Colonic ACF were induced by azoxymethane (AOM) (15 mg/kg BW once weekly for 2 weeks by s.c. injection at the age of 8 and 9 weeks). One week after AOM-treatment groups of rats were fed AIN-76A diet containing 0, 75, 150 and 300 ppm OSU-HDAC42 for eight-weeks, and then colonic ACF were evaluated. Six week-old male C57Bl/6J-APCmin/+ and wild type mice were fed AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm SAHA for 80 days. At ∼120 days of age, all mice were killed, and the intestines were evaluated for polyps. Dietary administration of OSU-HDAC42 produced a dose-dependent inhibition of AOM-induced colonic ACF formation (by 13-50%, p<0.05 -0.001) and reduced the number of foci with ≥4 crypts/focus (by 25-57%, P<0.05-0.0001) in F344 rats. 150 ppm OSU-HDAC42 significantly inhibited development of small intestinal (>46%, p<0.001) and colon tumors (>26%, P≥0.05) in APCmin/+ mice. Whereas 300 ppm SAHA showed limited non-significant inhibition of intestinal polyp formation in APCmin/+ mice. Further, OSU-HDAC42 showed inhibition in small intestinal polyps size measuring 1-2-mm (P<0.001). Importantly, mice fed with 150ppm OSU-HDAC42 showed significant reduction in HDAC-2, PCNA, CyclinA, CDK2, CDC25C expression pattern and increased p53 expression levels. These observations demonstrate that novel HDAC inhibitor, OSU-HDAC42 potential chemopreventive against the chemically-induced and polyposis models of colon tumorigenesis. {This work is supported by NCI-N01-CN53300} Citation Format: Durgadevi Ravillah, Li Qian, Misty Brewer, Yuting Zhang, Laura Biddick, Venkateshwar Madka, Jagan M.R. Patlolla, Altaf Mohammed, Vernon Steele, Chintalapally V. Rao. Targeting HADC-2: Chemopreventive effect of OSU-HDAC42 on rat colon carcinogenesis and APCmin/+ Mice intestinal tumorigenesis. [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 4392. doi:10.1158/1538-7445.AM2013-4392