title: Histone deacetylase inhibitors in castration-resistant prostate cancer: molecular mechanism of action and recent clinical trials.
abstract: Historically, androgen-deprivation therapy has been the cornerstone for treatment of metastatic prostate cancer. Unfortunately, nearly majority patients with prostate cancer transition to the refractory state of castration-resistant prostate cancer (CRPC). Newer therapeutic agents are needed for treating these CRPC patients that are unresponsive to androgen deprivation and/or chemotherapy. The histone deacetylase (HDAC) family of enzymes limits the expression of genomic regions by improving binding between histones and the DNA backbone. Modulating the role of HDAC enzymes can alter the cell's regulation of proto-oncogenes and tumor suppressor genes, thereby regulating potential neoplastic proliferation. As a result, histone deacetylase inhibitors (HDACi) are now being evaluated for CRPC or chemotherapy-resistant prostate cancer due to their effects on the expression of the androgen receptor gene. In this paper, we review the molecular mechanism and functional target molecules of different HDACi as applicable to CRPC as well as describe recent and current clinical trials involving HDACi in prostate cancer. To date, four HDAC classes comprising 18 isoenzymes have been identified. Recent clinical trials of vorinostat, romidepsin, and panobinostat have provided cautious optimism towards improved outcomes using these novel therapeutic agents for CPRC patients. Nevertheless, no phase III trial has been conducted to cement one of these drugs as an adjunct to androgen-deprivation therapy. Consequently, further investigation is necessary to delineate the benefits and drawbacks of these medications.
authors.affiliation: Department of Urology, University of Texas Health Science Center and Cancer Therapy and Research Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
authors.forename: Dharam
authors.initials: D
authors.lastname: Kaushik
authors.affiliation: Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Vashistha
authors.affiliation: Section of Urology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Isharwal
authors.affiliation: Department of Internal Medicine, MetroHealth Medical Center, Cleveland, OH, USA.
authors.forename: Soud A
authors.initials: SA
authors.lastname: Sediqe
authors.affiliation: Section of Urology, and Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
keywords: castration-resistant prostate cancer; clinical trials; histone deacetylase inhibitors