Oncotarget

Research Papers:

Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model

David J. McCarty, Weiliang Huang, Maureen A. Kane, Puranik Purushottamachar, Lalji K. Gediya and Vincent C.O. Njar _

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Oncotarget. 2017; 8:88501-88516. https://doi.org/10.18632/oncotarget.19762

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Abstract

David J. McCarty1,2, Weiliang Huang3, Maureen A. Kane3, Puranik Purushottamachar1,2, Lalji K. Gediya1,2 and Vincent C.O. Njar1,2,4

1Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA

2Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA

3Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA

4Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA

Correspondence to:

Vincent C.O. Njar, email: vnjar@som.umaryland.edu

Keywords: CWR22Rv1, apoptosis, AR-V7, prostate cancer, unfolded protein response

Received: May 17, 2017     Accepted: July 06, 2017     Published: August 01, 2017

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.


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