title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Kwegyir-Afful
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
authors.forename: Senthilmurugan
authors.initials: S
authors.lastname: Ramalingam
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
authors.forename: Vidya P
authors.initials: VP
authors.lastname: Ramamurthy
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.|Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000730:Androstadienes / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis; D001562:Benzimidazoles / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000730:Androstadienes; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C000609869:VNPT55; D045304:Cytochromes c; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; D046988:Proteasome Endopeptidase Complex; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
keywords: androgen receptors (AR/AR-V7); galeterone (gal); gal’s analog VNPT55; mechanisms of AR/AR-V7 degradation; prostate cancer