Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms.

Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspase-dependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

Finding the place of histone deacetylase inhibitors in prostate cancer therapy.

Histone deacetylase inhibitors (HDACIs) are showing promise as therapeutic agents for hematological malignancies and solid tumors. In the case of prostate cancer, HDACIs are effective at inhibiting proliferation and inducing apoptosis in a range of in vitro and in vivo experimental models. Recent studies have revealed that the actions of HDACIs in prostate cancer cells extend beyond regulation of histone acetylation and affect proteins involved in maintaining cellular homeostasis and tumor progression, including the androgen receptor, p21(WAF1) and VEGF. The broad spectrum of HDACI targets has allowed rational design of combinations with other therapeutic agents to target multiple pathways involved in prostate cancer progression, including angiogenesis and androgen signaling. In particular, synergistic inhibition of prostate cancer cell growth has been demonstrated using HDACIs in combination with radio- and chemo-therapy, Apo2L/TRAIL, angiogenesis inhibitors, heat-shock protein 90 inhibitors and androgen receptor antagonists. This review examines the current understanding of the actions of HDACIs in prostate cancer cells, both in a laboratory and a clinical context and discusses the potential utility of combination strategies for the treatment of prostate cancer.