RT Journal Article
SR Electronic
T1 Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease HSP90 and the Androgen Receptor Levels and Inhibit Viability in Enzalutamide Resistant C4-2 Prostate Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.116.103416
DO 10.1124/mol.116.103416
A1 Rayna Rosati
A1 Bailing Chen
A1 Mugdha Patki
A1 Thomas McFall
A1 Siyu Ou
A1 Elisabeth Heath
A1 Manohar Ratnam
A1 Zhihui Qin
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/07/05/mol.116.103416.abstract
AB Histone deacetylase (HDAC) inhibitors (HDACi) can disrupt viability of prostate cancer (PCa) cells through modulation of the cytosolic androgen receptor (AR) chaperone protein HSP90. However, toxicities associated with their pleiotropic effects could contribute to the ineffectiveness of HDACi in PCa treatment. We designed hybrid molecules containing partial chemical scaffolds of enzalutamide and suberoylanilide hydroxamic acid (SAHA), with weakened intrinsic pan-HDACi activities, to target HSP90 and AR in enzalutamide-resistant PCa cells. The potency of the new molecules (2-75 and 1005) as inhibitors of nuclear and cytosolic HDACs was substantially lower than that of SAHA in cell-free and in situ assays. 2-75 and 1005 antagonized gene activation by androgen without inducing chromatin association of AR. Enzalutamide had no effect on the levels of AR or HSP90 whereas the hybrid compounds induced degradation of both AR and HSP90, similar to (1005) or more potently than (2-75) SAHA. Similar to SAHA, 2-75 and 1005 decreased the level of HSP90 and induced acetylation in a predicted ~55 KDa HSP90 fragment. Compared to SAHA, 2-75 induced greater hyper-acetylation of the HDAC6 substrate alpha-tubulin but in contrast to SAHA neither hybrid molecule caused substantial hyper-acetylation of histones H3 and H4. 2-75 and 1005 induced p21 and caused loss of viability in the enzalutamide-resistant C4-2 cells with efficacies that were comparable to or better than SAHA. The results suggest the potential of the new compounds as prototype antitumor drugs that would downregulate HSP90 and AR in enzalutamide-resistant prostate cancer cells with weakened effects on nuclear HDACi targets.