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

Rui Li, Kristen Evaul, Kamalesh K. Sharma, Kai Hsiung Chang, Jennifer Yoshimoto, Jiayan Liu, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticle

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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 3bHSD 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 [ 3H]-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.

Original languageEnglish (US)
Pages (from-to)3571-3579
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number13
DOIs
StatePublished - Jul 1 2012

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3-Hydroxysteroid Dehydrogenases
Castration
Isomerases
Dehydroepiandrosterone
Androgen Receptors
Prostatic Neoplasms
Dihydrotestosterone
Pharmaceutical Preparations
Androstenedione
Heterografts
Growth
Androstenediol
Enzymes
Prostate-Specific Antigen
Hydroxyl Radical
Androgens
Genes
Testosterone
abiraterone
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Abiraterone inhibits 3β-hydroxysteroid dehydrogenase : A rationale for increasing drug exposure in castration-resistant prostate cancer. / Li, Rui; Evaul, Kristen; Sharma, Kamalesh K.; Chang, Kai Hsiung; Yoshimoto, Jennifer; Liu, Jiayan; Auchus, Richard J.; Sharifi, Nima.

In: Clinical Cancer Research, Vol. 18, No. 13, 01.07.2012, p. 3571-3579.

Research output: Contribution to journalArticle

Li, Rui ; Evaul, Kristen ; Sharma, Kamalesh K. ; Chang, Kai Hsiung ; Yoshimoto, Jennifer ; Liu, Jiayan ; Auchus, Richard J. ; Sharifi, Nima. / Abiraterone inhibits 3β-hydroxysteroid dehydrogenase : A rationale for increasing drug exposure in castration-resistant prostate cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 13. pp. 3571-3579.
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T2 - A rationale for increasing drug exposure in castration-resistant prostate cancer

AU - Li, Rui

AU - Evaul, Kristen

AU - Sharma, Kamalesh K.

AU - Chang, Kai Hsiung

AU - Yoshimoto, Jennifer

AU - Liu, Jiayan

AU - Auchus, Richard J.

AU - Sharifi, Nima

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N2 - 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 3bHSD 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 [ 3H]-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.

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