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Nature. 2015 Jul 16;523(7560):347-51. doi: 10.1038/nature14406. Epub 2015 Jun 1.

Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer.

Author information

1
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
2
1] Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
3
Department of Laboratory Medicine, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
4
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
5
1] Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
6
1] Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [3] Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Abstract

Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ(4)-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.

PMID:
26030522
PMCID:
PMC4506215
DOI:
10.1038/nature14406
[Indexed for MEDLINE]
Free PMC Article

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