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

Abstract

Background The progression of castration‐resistant prostate cancer (CRPC) still relies on the function of androgen receptor (AR), achieved by evolving mechanisms to reactivate AR signaling under hormonal therapy. Histone deacetylase inhibitors (HDACis) disrupt cytoplasmic AR chaperone heat shock protein 90 (Hsp90) via HDAC6 inhibition, leading to AR degradation and growth suppression of prostate cancer (PCa) cells. However, current HDACis are not effective in clinical trials treating CRPC. Methods We designed hybrid molecules containing partial chemical scaffolds of AR antagonist enzalutamide (Enz) and HDACi suberoylanilide hydroxamic acid (SAHA) as new anti‐PCa agents. We previously demonstrated that Enz‐HDACi hybrid drug 2‐75 targets both AR and Hsp90, which inhibits the growth of Enz‐resistant C4‐2 cells. In the current study, we further investigate the molecular and cellular actions of 2‐75 and test its anti‐PCa effects in vivo. Results Compared with Enz, 2‐75 had greater AR antagonistic effects by decreasing the stability, transcriptional activity, and nuclear translocation of intracellular AR. In addition to inhibition of full‐length AR (FL AR), 2‐75 downregulated the AR‐V7 variant in multiple PCa cell lines. Mechanistic studies indicated that the AR affinity of 2‐75 retains the drug in the cytoplasm of AR + PCa cells and further directs 2‐75 to the AR‐associated protein complex, which permits localized effects on AR‐associated Hsp90. Further, unlike pan‐HDACi SAHA, the cytoplasm‐retaining property allows 2‐75 to significantly inhibit cytoplasmic HDAC6 with limited impact on nuclear HDACs. These selective cytoplasmic actions of 2‐75 overcome the unfavorable resistance and toxicity properties associated with classical AR antagonists, HDACis, and Hsp90 inhibitors. Finally, 2‐75 showed greater antitumor activities than Enz in vivo on SQ xenografts derived from LNCaP cells. Conclusions Novel therapeutic strategy using newly designed 2‐75 and related AR antagonist‐HDACi hybrid drugs has great potential for effective treatment of CRPC.

HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

“…Several chimeric HDAC inhibitors with dual or multimodal activities were reported over the last years [29,30] . Compound 2-75 is a promising enzalutamide hybrid with HDAC inhibitory activity, which induced p21, led to higher acetyl-tubulin levels (based on stronger HDAC6 inhibition) than vorinostat, and suppressed Hsp90 and AR protein levels in C4-2 prostate cancer cells [74] . Based on these results, deeper studies of 2-75 in CRPC were carried out.…”

“…In vivo experiments with LNCaP tumor models revealed that 2-75 treatment (10 mg/kg, intratumoral injection twice weekly) had tumor growth inhibitory activity similar to enzalutamide, but, in the long run (after Day 24), 2-75 displayed improved tumor growth inhibition when compared with enzalutamide. The in vivo activity of 2-75 was accompanied by increased apoptosis induction and suppressed AR nuclear accumulation in the tumor bodies of treated mice [ 75 ] .…”

Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

“…In this study, the class I HDAC inhibitor MS-275 was found to not only promote the therapeutic effect of enzalutamide in the drug-sensitive LNCaP cell ( Figures 1C, 5B (a)) but also sensitize the drugresistant 22RV1 cells to enzalutamide treatment ( Figures 1D, 5B (b)). Consequently, gathering our and others recent data (Hu et al, 2019;Tang et al, 2019), we proposed that HDAC inhibitor could be useful in clinic cancer chemotherapy if an appropriate strategy was designed. In addition, AR was demonstrated to be a novel target of maspin which may reflect an additional characteristic of maspin for its anti-tumor activity and enriched its anti-tumor potency.…”

Inhibitors of histone deacetylase 6 based on a novel 3-hydroxy-isoxazole zinc binding group

“…The most active compounds 17 , 23 , 25 and 27 were tested in vitro in DU145, an androgen insensitive prostate cancer cell line (PCa) with very low or undetectable AR levels, which represents the castration-resistant PCa (CRPC) model. HDACs contribution to CRPC is known 20 and the possibility to arrest CRPC proliferation by acting on HDAC targets is expanding in the scientific literature 21 , 22 . After administration of the selected compounds for 24 h at 10 µM concentration, the effect on the acetylation levels of histone H3 and α-tubulin (respectively, HDAC1 and HDAC6 targets) was investigated.…”