Non-competitive androgen receptor inhibition in vitro and in vivo

Jeremy O. Jones, Eric C. Bolton, Yong Huang, Clementine Feau, R. Kiplin Guy, Keith R. Yamamoto, Byron Hann, Marc I. Diamond

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Androgen receptor (AR) inhibitors are used to treat multiple human diseases, including hirsutism, benign prostatic hypertrophy, and prostate cancer, but all available anti-androgens target only ligand binding, either by reduction of available hormone or by competitive antagonism. New strategies are needed, and could have an important impact on therapy. One approach could be to target other cellular mechanisms required for receptor activation. In prior work, we used a cell-based assay of AR conformation change to identify non-ligand inhibitors of AR activity. Here, we characterize 2 compounds identified in this screen: pyrvinium pamoate, a Food and Drug Administration-approved drug, and harmol hydrochloride, a natural product. Each compound functions by a unique, non-competitive mechanism and synergizes with competitive antagonists to disrupt AR activity. Harmol blocks DNA occupancy by AR, whereas pyrvinium does not. Pyrvinium inhibits AR-dependent gene expression in the prostate gland in vivo, and induces prostate atrophy. These results highlight new therapeutic strategies to inhibit AR activity.

Original languageEnglish (US)
Pages (from-to)7233-7238
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number17
DOIs
StatePublished - Apr 28 2009

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Androgen Receptors
Prostate
Prostatic Neoplasms
Hirsutism
Prostatic Hyperplasia
United States Food and Drug Administration
In Vitro Techniques
Biological Products
Androgens
Atrophy
Hormones
Ligands
Gene Expression
DNA
Therapeutics
Pharmaceutical Preparations
pyrvinium

Keywords

  • Antagonist
  • Harmol
  • Pyrvinium

ASJC Scopus subject areas

  • General

Cite this

Non-competitive androgen receptor inhibition in vitro and in vivo. / Jones, Jeremy O.; Bolton, Eric C.; Huang, Yong; Feau, Clementine; Guy, R. Kiplin; Yamamoto, Keith R.; Hann, Byron; Diamond, Marc I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 17, 28.04.2009, p. 7233-7238.

Research output: Contribution to journalArticle

Jones, Jeremy O. ; Bolton, Eric C. ; Huang, Yong ; Feau, Clementine ; Guy, R. Kiplin ; Yamamoto, Keith R. ; Hann, Byron ; Diamond, Marc I. / Non-competitive androgen receptor inhibition in vitro and in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 17. pp. 7233-7238.
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