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.

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

“…These are grouped into four different classes based on their homology to yeast and co-factor dependencies. Class I, II and IV are zinc-dependent metalloproteins, whereas class III uses NAD + as a co-factor ( Figure 2) [2]. Class II HDACs are longer in length and comprise a deacetylase domain in the C-terminal region, except for HDAC6 which possesses two deacetylase domains toward the N-terminal region [16].…”

“…There were~1.3 million new cases of prostate cancer worldwide in 2018 and it is the second most commonly diagnosed cancer in men [1]. Importantly, it ranks second among all cancer fatalities in males [2]. Even though the five-year survival for localized disease is 100%, it drops down to 29.3% if the prostate cancer metastasizes to other organs [3].…”

“…In advanced prostate cancer, androgen deprivation therapy, either by chemical castration in the form of luteinizing hormone-releasing hormone agonists/antagonists or surgical castration has typically been used. After a median of 18-24 months of treatment, most patients progress to a metastatic castration-resistant prostate cancer (CRPC) [6,7], which has a median survival time of 23-37 months [2]. Therefore, there is a need for novel therapeutic strategies that exploit the molecular signature of prostate cancers.…”

Targeting prostate cancer cells with enzalutamide‐HDAC inhibitor hybrid drug 2‐75

“…Mechanisms causing resistance include AR overexpression, gain‐of‐function AR mutation, expression of AR splice variants (AR‐Vs), and enhanced intratumoral androgen synthesis, and so forth; in addition, AR maintenance by heat shock proteins (Hsps) and AR transactivation assisted by histone deacetylases (HDACs) also play critical roles in sustained AR signaling . While this highlights a rationale for using HDAC inhibitors (HDACis) in PCa treatment, clinically available HDACis SAHA (vorinostat), romidepsin, and panobinostat only shows modest or inferior outcomes in CRPC trials as single‐agent therapy . Furthermore, over‐potent inhibition of nuclear HDACs (such as isoforms 1‐3) promotes numerous side effects including induction of epithelial‐mesenchymal transition (EMT) and upregulation of proinflammatory cytokines that stimulate tumor growth and aggressiveness .…”

“…6,7 While this highlights a rationale for using HDAC inhibitors (HDACis) in PCa treatment, clinically available HDACis SAHA (vorinostat), romidepsin, and panobinostat only shows modest or inferior outcomes in CRPC trials as single-agent therapy. 8 Furthermore, over-potent inhibition of nuclear HDACs (such as isoforms 1-3) promotes numerous side effects including induction of epithelial-mesenchymal transition (EMT) 9,10 and upregulation of proinflammatory cytokines that stimulate tumor growth and aggressiveness. 11,12 Therefore, selective cytoplasmic actions of HDACis are more desirable for treating CRPC.…”