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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.
AuthorsHidetoshi Kuruma, Hiroaki Matsumoto, Masaki Shiota, Jennifer Bishop, Francois Lamoureux, Christian Thomas, David Briere, Gerrit Los, Martin Gleave, Andrea Fanjul, Amina Zoubeidi
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 5 Pg. 567-76 (May 2013) ISSN: 1538-8514 [Electronic] United States
PMID23493310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2013 AACR
Chemical References
  • Androgen Antagonists
  • Antineoplastic Agents
  • Benzamides
  • Nitriles
  • Pyridinium Compounds
  • Receptors, Androgen
  • compound 30
  • Phenylthiohydantoin
  • enzalutamide
Topics
  • Androgen Antagonists (pharmacology)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Benzamides
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Male
  • Mice
  • Nitriles
  • Orchiectomy
  • Phenylthiohydantoin (analogs & derivatives, pharmacology)
  • Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Pyridinium Compounds (pharmacology)
  • Receptors, Androgen (genetics, metabolism)
  • Transcription, Genetic
  • Tumor Burden (drug effects)
  • Xenograft Model Antitumor Assays

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