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Histone Deacetylase-Inhibitors Sensitize Human Prostate Cancer Cell Lines to Growth Suppression and Apoptosis by Retinoids

Author(s): Jian Gu | Xianshi Zhao | Remco A. Spanjaard | Tai C. Chen | John N. Flanagan | Michael Boosalis | Susan P. Perrine | Douglas V. Faller

Journal: Journal of Cancer Molecules
ISSN 1816-0735

Volume: 2;
Issue: 1;
Start page: 25;
Date: 2006;
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Keywords: short-chain fatty acid | retinoic acid receptor | chemoprevention | cell cycle

AIM: Retinoids have achieved some promise as chemopreventive agents in aerodigestive cancers, and have potential activity in the chemoprevention of prostate cancer. Despite their anti-proliferative effects on prostate tumor cell lines in culture, however, the clinical use of retinoids in prostate cancer therapy has been limited by the frequent and unpredictable resistance of prostate tumors to retinoid actions. Transcription of retinoic acid (RA) target genes is suppressed by recruitment of histone deacetylases (HDACs) to the promoter region. This study is to investigate whether HDAC-inhibitors are potentially useful for the combination use with retinoids in prostate cancer.METHODS: To test the hypothesis that HDAC-inhibitors combined with retinoids would significantly enhance the functional activity of Retinoic Acid Receptors (RARs), and that this combination agent approach would exert a more profound cytostatic/differentiating effect on prostate cancer cells than either compound alone can achieve, we studied prostate cancer cell lines of different origins, and analyzed cellular proliferation, cell cycle profiles, differentiation, apoptosis, and retinoid responsiveness, after exposure to retinoids (all-trans and 9-cis retinoic acids and N-(4-hydroxy-phenyl)retinamide [4-HPR]) alone or in combination with butyrate or other HDAC-inhibitors.RESULTS: The combination of retinoids with HDAC-inhibitors generated significantly more apoptosis than did either agent alone in the cell lines studied. Synergistic induction of a transfected retinoid-responsive reporter gene, and of an endogenous prototypic retinoid-responsive gene, was stimulated by the combination of a HDAC-inhibitor plus retinoid. The transcript of a relevant retinoid receptor, RARĪ², was synergistically induced by the combination of agents.CONCLUSION: These findings suggest that the combination of a HDAC-inhibitor with a retinoid may be a useful therapeutic strategy for prostate cancer.
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