Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

Abstract

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer

“…Since HDAC inhibitors such as SAHA, panobinostat, pracinostat and romidepsin have failed in CRPC patients due to a lack of efficacy and toxicity, new treatments are urgently needed [7]. We have previously synthesised and characterised two novel HDACis, Jazz90 and Jazz167, which showed an improved selectivity index compared to SAHA (~2-fold) [22] and were superior in terms of inhibiting angiogenic markers (VEGF-A and VEGFR-2) in PC3 cells [22,23]. Therefore, these compounds were examined further for their ability to modulate angiogenesis and invasion.…”

“…These compounds were also potent HDAC inhibitors with activity superior to SAHA at reducing the expression levels of VEGF-A and VEGFR-2. Jazz90 was 4-fold more potent at inhibiting HDAC6, and Jazz167 was 2-, 4-and 40-fold more potent at inhibiting HDACs 1, 6 and 8 than SAHA [22,23].…”

“…Previously, we reported that Jazz90 and Jazz167 inhibited HDACs, induced the acetylation of histone-3 and had a cytostatic effect on PC3 and DU145 cells [23]. Jazz90 and Jazz167 also inhibited the expression of angiogenic markers such as vascular growth factor-A (VEGF-A) and vascular endothelial growth factor receptor-2 (VEGFR-2) in a 2D model of PC3 cells [22].…”

Biopolymer and Biomaterial Conjugated Iron Oxide Nanomaterials as Prostate Cancer Theranostic Agents: A Comprehensive Review

“…Symmetry as well as symmetry breaking could offer a novel approach to deal with the cancer problem. Prostate cancer (PCa) is the second most commonly diagnosed and the leading cause of death in men all over the world [1,2]. According to the American Chemical Society, over 0.6 million men died of PCa while Symmetry 2021, 13, 974 2 of 23 approximately 1.8 million men were diagnosed in 2020 [3].…”

Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor

“…However, severe drawbacks have emerged during the clinical application of single HDAC inhibitors such as intrinsic or acquired drug resistance. Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”