title: A novel antiandrogen, Compound 30, suppresses castration-resistant and MDV3100-resistant prostate cancer growth in vitro and in vivo.
abstract: Resistance to antiandrogen drugs, like MDV3100, occurs in patients with castration-resistant prostate cancer (CRPC). Thus, preventing or treating antiandrogen resistance is a major clinical challenge. We identified a novel antiandrogen, Compound 30, and compared its efficacy with MDV3100. We found that Compound 30 inhibits androgen receptor (AR) activity in LNCaP cells, C4-2 cells, as well as MDV3100-resistant cell lines. Compared with MDV3100, Compound 30 treatment induces greater reduction in AR, prostate-specific antigen (PSA), and AR transcriptional activity, and prevents AR nuclear translocation in AR-sensitive LNCaP cells. Compound 30 has antiproliferative effects in LNCaP cells, in castrate-resistant C4-2 cells, and those resistant to MDV3100. Compound 30 was equally as effective as MDV3100 in reducing tumor volume and PSA in vivo. More importantly, Compound 30 is effective at inhibiting AR activity in MDV3100-resistant cell lines and significantly prevented tumor growth and PSA increases in mice bearing MDV3100-resistant xenografts. Together, our data show that Compound 30 strongly inhibited AR activity and suppressed castration-resistant LNCaP growth as well as MDV3100-resistant cell growth in vitro and in vivo. These data provide a preclinical proof-of-principle that Compound 30 could be a promising next generation anti-AR agent, especially in the context of antiandrogen-resistant tumors.
authors.affiliation: The Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kuruma
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bishop
authors.forename: Francois
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Briere
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Andrea
authors.initials: A
authors.lastname: Fanjul
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011726:Pyridinium Compounds; D011944:Receptors, Androgen; C009863:compound 30; D010669:Phenylthiohydantoin; C540278:enzalutamide