Histone deacetylase inhibitors in castration-resistant prostate cancer: molecular mechanism of action and recent clinical trials

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.

[1]  Sanjay Gupta,et al.  The role of histone deacetylases in prostate cancer , 2008, Epigenetics.

[2]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[3]  H. Scher,et al.  Hsp90 as a therapeutic target in prostate cancer. , 2003, Seminars in oncology.

[4]  Wei Gu,et al.  Synergistic activation of transcription by CBP and p53 , 1997, Nature.

[5]  Y. E. Chin,et al.  Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue , 2005, Science.

[6]  Haishan Wang,et al.  Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics , 2011, Drug Metabolism and Disposition.

[7]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[8]  D. Robins,et al.  Hsp90 Regulates Androgen Receptor Hormone Binding Affinity in Vivo* , 1996, The Journal of Biological Chemistry.

[9]  D. Dearnaley,et al.  Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  Shafiq A. Khan,et al.  Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol , 2008, Molecular and Cellular Endocrinology.

[11]  P. Nelson,et al.  Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. , 2008, Cancer research.

[12]  S. Roy,et al.  Site-specific Acetylation of p53 Directs Selective Transcription Complex Assembly* , 2007, Journal of Biological Chemistry.

[13]  T. Golub,et al.  Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. , 2006, Cancer research.

[14]  E. Appella,et al.  Post-translational modifications and activation of p53 by genotoxic stresses. , 2001, European journal of biochemistry.

[15]  M. Lübbert,et al.  Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy , 2010, Clinical Epigenetics.

[16]  E. Eisenhauer,et al.  A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195 , 2015, Investigational New Drugs.

[17]  V. Castronovo,et al.  Screening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class I HDAC profiles between epithelial and stromal cells. , 2004, European journal of histochemistry : EJH.

[18]  P. Atadja,et al.  Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824 , 2005, Molecular Cancer Therapeutics.

[19]  Eric Verdin,et al.  Duration of Nuclear NF-κB Action Regulated by Reversible Acetylation , 2001, Science.

[20]  L. Neckers,et al.  Heat shock protein 90 , 2003, Current opinion in oncology.

[21]  Z. Bonday,et al.  SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer , 2010, Molecular Cancer Therapeutics.

[22]  Zigang Dong,et al.  Post-translational modification of p53 in tumorigenesis , 2004, Nature Reviews Cancer.

[23]  P. Atadja,et al.  A phase I study of oral panobinostat (LBH589) alone and in combination with docetaxel (Doc) and prednisone in castration-resistant prostate cancer (CRPC) , 2008 .

[24]  W. Weichert,et al.  Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy , 2008, British Journal of Cancer.

[25]  Wei Gu,et al.  Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain , 1997, Cell.

[26]  Ching-Yu Chen,et al.  Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. , 2007, Cancer research.

[27]  S. Kulp,et al.  Antitumor Effects of a Novel Phenylbutyrate-Based Histone Deacetylase Inhibitor, (S)-HDAC-42, in Prostate Cancer , 2006, Clinical Cancer Research.

[28]  L. Neckers,et al.  Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. , 2002, Journal of the National Cancer Institute.

[29]  K. Pienta,et al.  The Current State of Hormonal Therapy for Prostate Cancer , 2002, CA: a cancer journal for clinicians.

[30]  B. Hemmings,et al.  Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. , 2010, Current topics in microbiology and immunology.

[31]  H. Scher,et al.  A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer , 2013, Cancer Chemotherapy and Pharmacology.

[32]  S. Shankar,et al.  Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis. , 2008, Advances in experimental medicine and biology.