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OSU-HDAC42, a Histone Deacetylase Inhibitor, Blocks Prostate Tumor Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

¹ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, ² Department of Veterinary Biosciences, College of Veterinary Medicine, ³ Division of Hematology and Oncology, College of Medicine, and ⁴ Department of Human Nutrition, College of Education and Human Ecology, The Ohio State University, Columbus, Ohio

Requests for reprints: Ching-Shih Chen, College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210-1291. Phone: 614-688-4008; Fax: 614-688-8556; E-mail: chen.844{at}osu.edu.

Key Words: TRAMP • prostate • OSU-HDAC42 • histone deacetylase • chemoprevention

Histone deacetylase (HDAC) inhibitors suppress tumor cell growth via a broad spectrum of mechanisms, which should prove advantageous in the context of cancer prevention. Here, we examined the effect of dietary administration of OSU-HDAC42, a novel HDAC inhibitor, on prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Based on a series of pilot studies, an AIN-76A diet was formulated containing 208 ppm OSU-HDAC42, which was estimated to deliver 25 mg/kg of drug per day to each mouse and found to cause a suppression of PC-3 xenograft tumor growth equivalent to that achieved by gavage administration of a similar dose. At 6 weeks of age, TRAMP mice received this drug-containing or control diet for 4 or 18 weeks and were evaluated for prostatic intraepithelial neoplasia (PIN) and carcinoma development, respectively. OSU-HDAC42 not only decreased the severity of PIN and completely prevented its progression to poorly differentiated carcinoma (74% incidence in controls versus none in drug-treated mice), but also shifted tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively, at 24 weeks of age. This tumor suppression was associated with the modulation of intraprostatic biomarkers, including those indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. With the exception of completely reversible hematologic alterations and testicular degeneration, no significant changes in body weight or other indicators of general health were observed in drug-treated mice. These results suggest that OSU-HDAC42 has value in prostate cancer prevention. [Cancer Res 2008;68(10):3999–4009]