Abstract
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
Highlights
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]
HDAC1 and HDAC3, the results demonstrated that the PSA (Prostate-Specific Antigen)-relapse-free statistically data were not obtained for HDAC1 and HDAC3, the results demonstrated survival was significant decreased in Histone deacetylase (HDAC)-positive cells compared to -negative cells [20]
Two layers of information are lacking in studies conducted on HDAC inhibitors in cancer
Summary
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]. There is a need for novel therapeutic strategies that exploit the molecular signature of prostate cancers One of these strategies involves modulating histone acetylation and deacetylation mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs), respectively. HDAC3 levels did not expression between prostate cancer and normal prostate parenchyma Other types of HDAC were not tested in this particular database for cancers, Oncomine, correspond with results from the aforementioned study conducted by study. Inhibition results in a differential expression of genes involved in cytoskeleton remodeling, chromatin assembly and transcription, WNT and PPAR-signaling pathways. Only one study has failed to show a difference in the expression of either HDAC1 or HDAC2 between cancerous and normal tissues [55].
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