Non-steroidal antiandrogens act as AF-1 agonists under conditions of high androgen-receptor expression

Prostate. 2007 May 1;67(6):630-7. doi: 10.1002/pros.20269.


Background: The mechanism of resistance acquisition to antiandrogens in prostate cancer is not fully understood. Numerous clinical and basic research studies have shown expression of androgen receptors (ARs) increases in hormone-refractory prostate cancer and therefore we explored possible molecular mechanisms by which prostate cancer acquires resistance to antiandrogens under conditions of increased AR expression.

Methods: In order to study resistance to antiandrogens at the AR transactivation level we used a human AR (hAR) reporter assay system. In addition, we utilized an hAR deletion mutant to determine the functional domain responsible for the acquisition of resistance.

Results: Increased hAR protein expression enhanced the sensitivity of AR transactivation to low concentrations of DHT, and also reduced the inhibitory activity of the non-steroidal antiandrogens, hydroxyflutamide, and bicalutamide on DHT-induced AR transactivation. Moreover, these antiandrogens acquired agonistic activity under conditions of high hAR protein expression. Such agonistic activity of antiandrogens was not detected in an hAR deletion mutant (hAR-DeltaA/B) that lacked an A/B domain with AF-1 activity.

Conclusions: We found that non-steroidal antiandrogens act as AF-1 agonists under conditions of high AR protein expression. This partial antagonistic property of antiandrogens may be a molecular mechanism by which prostate cancer develops resistance to these drugs.

MeSH terms

  • Androgens / pharmacology
  • Anilides / pharmacology*
  • Dihydrotestosterone / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Flutamide / analogs & derivatives*
  • Flutamide / pharmacology
  • HeLa Cells
  • Humans
  • Male
  • Nitriles / pharmacology*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Receptors, Androgen / deficiency
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Receptors, Interferon / agonists*
  • Receptors, Interferon / metabolism
  • Tosyl Compounds / pharmacology*
  • Transcriptional Activation / drug effects*


  • AR protein, human
  • Androgens
  • Anilides
  • IFNGR2 protein, human
  • Nitriles
  • Receptors, Androgen
  • Receptors, Interferon
  • Tosyl Compounds
  • Dihydrotestosterone
  • hydroxyflutamide
  • Flutamide
  • bicalutamide