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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • Abiraterone Acetate
  • Active Transport, Cell Nucleus
  • Androstadienes / pharmacology*
  • Androstadienes / therapeutic use
  • Androstenedione / biosynthesis
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Dehydroepiandrosterone / metabolism
  • Dihydrotestosterone / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Orchiectomy
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / metabolism
  • Testosterone / biosynthesis
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Androstadienes
  • Antineoplastic Agents
  • Isoenzymes
  • Receptors, Androgen
  • Dihydrotestosterone
  • Testosterone
  • Androstenedione
  • Dehydroepiandrosterone
  • 3-Hydroxysteroid Dehydrogenases
  • Abiraterone Acetate