title: Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer.
abstract: The next-generation antiandrogen MDV3100 prolongs overall survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patient responses are variable, and survival benefit remains relatively small. Developing effective modality to improve MDV3100 efficacy is urgently needed. Recent evidence suggests that constitutively active androgen receptor splice variants (AR-Vs) drive resistance to MDV3100. In our study, we show that methylselenol prodrug downregulates the expression and activity of both the full-length AR (AR-FL) and AR-Vs. The downregulation is independent of androgen and could be attributable to repressed transcription of the AR gene. Cotreatment with methylselenol prodrug and MDV3100 suppresses AR signaling more dramatically than either agent alone, and synergistically inhibits the growth of CRPC cells in vitro. The combinatorial efficacy is observed in not only AR-V-expressing cells but also cells expressing predominantly AR-FL, likely owing to the ability of the two drugs to block the AR signaling cascade at distinct steps. Ectopic expression of AR-FL or AR-V7 attenuates the combinatorial efficacy, indicating that downregulating AR-FL and AR-V7 is importantly involved in mediating the combinatorial efficacy. Significantly, methylselenol prodrug also downregulates AR-FL and AR-Vs in vivo and substantially improves the antitumor efficacy of MDV3100. These findings support a potential combination therapy for improving MDV3100 efficacy, and provide a rationale for evaluating the clinical application of combining methylselenol prodrug with MDV3100 for the treatment of CRPC.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhan
authors.forename: Bo
authors.initials: B
authors.lastname: Cao
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Qi
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhou
authors.forename: Duo
authors.initials: D
authors.lastname: Xu
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D045744:Cell Line, Tumor; D002855:Chromatography, Thin Layer; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D000432:Methanol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles; D009919:Orchiectomy; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D011944:Receptors, Androgen / Q000235:genetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D001549:Benzamides; D004273:DNA, Neoplasm; D009570:Nitriles; D016566:Organoselenium Compounds; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C019003:methaneselenol; C540278:enzalutamide; D000432:Methanol
keywords: MDV3100; androgen receptor; castration-resistant prostate cancer; methylseleninic acid; methylselenocysteine