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Abstract
The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility.Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide. However, induction of apoptosis in these models is independent of the AR and its truncated variant, AR-V7, and instead likely results from sustained endoplasmic reticulum stress and deregulated calcium homeostasis. Using in silico molecular docking, we predict VNPT-178 and VNLG-74A bind the ATPase domain of BiP/Grp78 and Hsp70-1A with greater affinity than the AR.Disruption of 70 kDa heat shock protein function may be the underlying mechanism of action for these galeterone analogs. Therefore, despite simultaneously antagonizing AR activity, AR and/or AR-V7 expression alone may inadequately predict a patient’s response to treatment with VNPT-178 or VNLG-74A. Future studies evaluating the context-specific limitations of these compounds may provide clarity for their clinical application.
Highlights
Prostate cancer (PC) is among the most frequently diagnosed and lethal malignancies in American men [1]
Using an MTT assay to measure dosedependent changes in viable cell populations after six days of treatment, VNPT-178 and VNLG-74A demonstrated improved potencies compared to abiraterone and enzalutamide (Figure 1B plots) with 50 and 90% growth inhibitory (GI50 and GI90) concentrations estimated in the low micromolar range (Figure 1B table summary)
Both VNPT-178 and VNLG-74A elicit similar responses in all three cell lines while the ARnegative prostate cancer (PC)-3 cells are markedly resistant to abiraterone and enzalutamide
Summary
Prostate cancer (PC) is among the most frequently diagnosed and lethal malignancies in American men [1]. While increased early detection combined with surgical or radiological treatment of localized tumors has significantly improved the overall survival rate, most men treated with systemic therapies (e.g. castration) targeting advanced or metastatic tumors develop resistance. New approaches are necessary to combat the progression of these lesions to the lethal phenotype referred to as castrationresistant prostate cancer (CRPC). The androgen receptor (AR) is a transcription factor belonging to the nuclear hormone family of receptors and continues as the primary target for PC drug development as its role in the maintenance of PC tumors in all stages of progression is well-documented [2]. Abiraterone acetate (Zytiga) and enzalutamide (Xtandi), the two most-recent AR-directed therapies to gain FDA approval for treatment of PC, are completely ineffective in men presenting with AR-V7-expressing tumors [3]
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