TY - JOUR T1 - Chemopreventive Effects of an HDAC2-Selective Inhibitor on Rat Colon Carcinogenesis and APC<sup>min/+</sup> Mouse Intestinal Tumorigenesis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 59 LP - 68 DO - 10.1124/jpet.113.208645 VL - 348 IS - 1 AU - Durgadevi Ravillah AU - Altaf Mohammed AU - Li Qian AU - Misty Brewer AU - Yuting Zhang AU - Laura Biddick AU - Vernon E. Steele AU - Chinthalapally V. Rao Y1 - 2014/01/01 UR - http://jpet.aspetjournals.org/content/348/1/59.abstract N2 - Epigenetic modulators, particularly histone deacetylases (HDACs), are valid targets for cancer prevention and therapy. Recent studies report that HDAC2 overexpression is associated with colon tumor progression and is a potential target for colon cancer prevention. This study tested chemopreventive and dose-response effects of Ohio State University HDAC42 (OSU-HDAC42), a selective HDAC2 inhibitor, using a rat colon carcinogenesis model to assess aberrant crypt foci inhibition and a familial adenomatous polyposis model to assess intestinal tumor inhibition. Colonic aberrant crypt foci were induced by azoxymethane (AOM) (15 mg/kg body weight, once-weekly subcutaneous injections at 8 and 9 weeks age). One week after AOM treatment, groups of rats were fed an AIN-76A diet containing 0, 75, 150, and 300 ppm OSU-HDAC42 for 8 weeks, and colonic aberrant crypt foci were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small-intestinal polyps and colon tumor growth, 6-week-old male C57Bl/6J-APCmin/+mice were fed an AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm pan-HDAC inhibitor suberoylanilide hydroxyamic acid (SAHA) for 80 days. Our results demonstrate that dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic aberrant crypt foci formation (13–50%; P &lt; 0.01 to &lt; 0.0001) and reduced multiple crypts with ≥4 crypts per focus (25–57%; P &lt; 0.01 to &lt; 0.0001) in F344 rats. Our findings show that 150 ppm OSU-HDAC42 significantly inhibited small-intestinal polyps (&gt;46%; P &lt; 0.001), with polyp size measuring &gt;1 mm (P &lt; 0.001), and colon tumors (&gt;26%) in APCmin/+mice, whereas 300 ppm SAHA showed nonsignificant inhibition. Mice fed 150 ppm OSU-HDAC42 had significantly decreased HDAC2, proliferating cell nuclear antigen, B cell lymphoma 2, cyclin-dependent kinase 2, and cell division cycle homolog 25C expression levels and increased p53 expression levels. These observations demonstrate the chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal tumorigenesis. ER -