Research Papers:

Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo

Andrew K. Kwegyir-Afful, Senthilmurugan Ramalingam, Puranik Purushottamachar, Vidya P. Ramamurthy and Vincent C. O. Njar _

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Oncotarget. 2015; 6:27440-27460. https://doi.org/10.18632/oncotarget.4578

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Andrew K. Kwegyir-Afful1,2, Senthilmurugan Ramalingam1,2, Puranik Purushottamachar1,2, Vidya P. Ramamurthy1,2, Vincent C.O. Njar1,2,3

1Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA

2Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA

3Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA

Correspondence to:

Vincent C.O. Njar, e-mail: [email protected]

Keywords: prostate cancer, androgen receptors (AR/AR-V7), galeterone (gal), gal’s analog VNPT55, mechanisms of AR/AR-V7 degradation

Received: June 16, 2015     Accepted: July 03, 2015     Published: July 14, 2015


Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/ARv567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy.

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