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Clin Cancer Res. 2012 Jul 1;18(13):3571-9. doi: 10.1158/1078-0432.CCR-12-0908.

Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer.

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  • 1Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

PURPOSE:

Treatment with abiraterone (abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to upregulation of steroidogenic enzymes and/or other mechanisms that sustain dihydrotestosterone (DHT) synthesis, which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. On the basis of the 3β-hydroxyl, Δ(5)-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for DHT synthesis in CRPC, regardless of origins or routes of synthesis.

EXPERIMENTAL DESIGN:

We tested the effects of abi on 3βHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.

RESULTS:

Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [(3)H]-dehydroepiandrosterone (DHEA) to Δ(4)-androstenedione, androgen receptor nuclear translocation, expression of androgen receptor-responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of Δ(5)-androstenediol to testosterone by 3βHSD. Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC(50) value of less than 1 μmol/L in CRPC cell lines; inhibits androgen receptor nuclear translocation; expression of TMPRSS2, prostate-specific antigen, and FKBP5; and decreases CRPC xenograft growth in DHEA-supplemented mice.

CONCLUSIONS:

We conclude that abi inhibits 3βHSD-mediated conversion of DHEA to active androgens in CRPC. This second mode of action might be exploited to reverse resistance to CYP17A1 inhibition at the standard abi dose by dose-escalation or simply by administration with food to increase drug exposure.

©2012 AACR.

PMID:
22753664
[PubMed - indexed for MEDLINE]
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