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

Hiroaki Fuse1, Shigeru Korenaga, Matomo Sakari

  • 1Pharmacological Research Department, ASKA Pharmaceutical Co. Ltd., Takatsu-ku, Kawasaki, Kanagawa, Japan. fuse-h@aska-pharma.co.jp

The Prostate
|March 8, 2007
PubMed
Abstract

Insights

Prostate cancer resistance to antiandrogens may occur when increased androgen receptor (AR) expression causes these drugs to act as agonists. This finding sheds light on treatment resistance mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The mechanisms by which prostate cancer develops resistance to antiandrogen therapies are not fully elucidated.
  • Increased expression of androgen receptors (ARs) is observed in hormone-refractory prostate cancer.

Purpose of the Study:

  • To investigate molecular mechanisms of antiandrogen resistance in prostate cancer under conditions of elevated AR expression.
  • To explore the role of AR transactivation in acquired resistance to antiandrogens.

Main Methods:

  • Utilized a human AR (hAR) reporter assay system to study antiandrogen resistance at the AR transactivation level.
  • Employed an hAR deletion mutant to identify the functional domain responsible for resistance acquisition.

Main Results:

  • Elevated hAR protein expression increased AR transactivation sensitivity to DHT and reduced the inhibitory effects of hydroxyflutamide and bicalutamide.
  • Non-steroidal antiandrogens exhibited agonistic activity at high hAR protein levels.
  • This agonistic activity was absent in an hAR deletion mutant lacking the A/B domain with AF-1 activity.

Conclusions:

  • Non-steroidal antiandrogens function as AF-1 agonists when AR protein expression is high.
  • This partial agonistic property of antiandrogens represents a potential molecular mechanism for prostate cancer drug resistance.

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