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.
Highlights
1.3 million new cases of prostate cancer were diagnosed in 2018, making it the second-most commonly diagnosed cancer and cause of fatalities in men [1]
Given that Histone deacetylases (HDACs) feature a zinc (II) ion in the active site, ligand docking predicted that Jazz90 can bind to HDACs via either the hydroxamic acid or pyridinecarbothioamide moiety
Pyridinecarbothioamides have not been shown to have metalloenzyme inhibitory activity, and further assessment of the structure–activity relationship via replacing the hydroxamate acid in Jazz90 shall give a better insight into the potential of pyridine carbothioamide for zinc coordination in HDAC
Summary
1.3 million new cases of prostate cancer were diagnosed in 2018, making it the second-most commonly diagnosed cancer and cause of fatalities in men [1]. 2005, a 66% increase in the incidence of prostate cancer has been observed due to an aging population [1,2]. Prostate cancer is dependent on serum androgen levels, and androgen deprivation therapy is effective [3]. After a median time of 18–24 months, the majority of patients develop castration-resistant prostate cancer (CRPC), where tumors grow in the absence of androgens, even though androgen receptors (ARs) are present [4,5]. 11–24% of patients develop this phenotype [6,9] and become resistant to enzalutamide, a Food and
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