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Research Articles: Therapeutics, Targets, and Development

Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation

¹ Dame Roma Mitchell Cancer Research Laboratories, Department of Medicine, University of Adelaide, Hanson Institute, Adelaide, South Australia, Australia; ² Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, South Australia, Australia; ³ Genitourinary Oncology Service, and ⁴ Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁵ Merck & Co., Inc., Boston, Massachusetts

Requests for reprints: Lisa M. Butler, Dame Roma Mitchell Cancer Research Laboratories, Department of Medicine, University of Adelaide, Hanson Institute, Adelaide, South Australia 5000, Australia. Phone: 618-8222-3270; Fax: 618-8222-3217. E-mail: lisa.butler{at}imvs.sa.gov.au

Abstract

Growth of prostate cancer cells is initially dependent on androgens, and androgen ablation therapy is used to control tumor growth. Unfortunately, resistance to androgen ablation therapy inevitably occurs, and there is an urgent need for better treatments for advanced prostate cancer. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA; vorinostat), are promising agents for the treatment of a range of malignancies, including prostate cancer. SAHA inhibited growth of the androgen-responsive LNCaP prostate cancer cell line at low micromolar concentrations and induced caspase-dependent apoptosis associated with chromatin condensation, DNA fragmentation, and mitochondrial membrane depolarization at higher concentrations (5 µmol/L). Gene profiling and immunoblot analyses showed a decrease in androgen receptor (AR) mRNA and protein in LNCaP cells cultured with SAHA compared with control cells, with a corresponding decrease in levels of the AR-regulated gene, prostate-specific antigen. Culture of LNCaP cells in steroid-free medium markedly sensitized the cells to SAHA. Moreover, a combination of low, subeffective doses of SAHA and the AR antagonist bicalutamide resulted in a synergistic reduction in cell proliferation and increase in caspase-dependent cell death. Addition of exogenous androgen prevented the induction of cell death, indicating that suppression of androgen signaling was required for synergy. At the subeffective concentrations, these agents had no effect, alone or in combination, on proliferation or death of AR-negative PC-3 prostate cancer cells. Our findings indicate that SAHA is effective in targeting the AR signaling axis and that androgen deprivation sensitizes prostate cancer cells to SAHA. Consequently, combinatorial treatments that target different components of the AR pathway may afford a more effective strategy to control the growth of prostate cancer cells. [Mol Cancer Ther 2007;6(1):51–60]

Grant support: Burke Foundation (L.M. Butler and H.I. Scher); the Japan Foundation for Cancer Research, the DeWitt Wallace Fund for Memorial Sloan-Kettering Cancer Center, the David H. Koch Prostate Cancer Research Award, and NIH grant CA-0974823 (P.A. Marks and R.A. Rifkind); the Prostate Cancer Foundation of Australia (L.M. Butler); and the National Health and Medical Research Council of Australia grant 299048 (L.M. Butler and W.D. Tilley).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Disclosure statement: Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold the patents on the hydroxamic acid–based hybrid polar compounds, including suberoylanilide hydroxamic acid, which are exclusively licensed to Aton Pharmaceuticals, Inc. of which Richard A. Rifkind, Paul A. Marks, and Victoria M. Richon are founders. Aton Pharma is a wholly-owned subsidiary of Merck & Co. Both Memorial Sloan-Kettering Cancer Center, Columbia University, and the founders had an equity position in Aton Pharmaceuticals.

⁶ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/17/06; revised 10/ 6/06; accepted 11/16/06.

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