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Prostate Cancer Prostatic Dis. 2014 Sep;17(3):292-9. doi: 10.1038/pcan.2014.27. Epub 2014 Jul 22.

Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate.

Author information

  • 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 2Department of Molecular Pharmacology, City of Hope, Duarte, CA, USA.
  • 3Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
  • 4Atara Biotherapeutics, Westlake Village, CA, USA.
  • 5Janssen Research and Development, Los Angeles, CA, USA.

Abstract

BACKGROUND:

Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells.

METHODS:

Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells.

RESULTS:

Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients.

CONCLUSIONS:

Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.

PMID:
25047002
[PubMed - in process]
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