PMID- 26030522 OWN - NLM STAT- MEDLINE DCOM- 20160301 LR - 20220410 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 523 IP - 7560 DP - 2015 Jul 16 TI - Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. PG - 347-51 LID - 10.1038/nature14406 [doi] AB - Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5alpha-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 3beta-hydroxysteroid dehydrogenase (3betaHSD), steroid-5alpha-reductase (SRD5A) and 17beta-hydroxysteroid dehydrogenase (17betaHSD) isoenzymes. Abiraterone, a steroidal 17alpha-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 Delta(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, 3betaHSD 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. FAU - Li, Zhenfei AU - Li Z AD - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. FAU - Bishop, Andrew C AU - Bishop AC AD - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. FAU - Alyamani, Mohammad AU - Alyamani M AD - Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. FAU - Garcia, Jorge A AU - Garcia JA AD - 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. FAU - Dreicer, Robert AU - Dreicer R AD - 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. FAU - Bunch, Dustin AU - Bunch D AD - Department of Laboratory Medicine, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. FAU - Liu, Jiayan AU - Liu J AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. FAU - Upadhyay, Sunil K AU - Upadhyay SK AD - Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. FAU - Auchus, Richard J AU - Auchus RJ AD - 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. FAU - Sharifi, Nima AU - Sharifi N AD - 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. LA - eng GR - R01 CA168899/CA/NCI NIH HHS/United States GR - R01CA190289/CA/NCI NIH HHS/United States GR - R01 CA190289/CA/NCI NIH HHS/United States GR - R01CA168899/CA/NCI NIH HHS/United States GR - L30 CA135719/CA/NCI NIH HHS/United States GR - Howard Hughes Medical Institute/United States GR - R01CA172382/CA/NCI NIH HHS/United States GR - R01 CA172382/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20150601 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (5-alpha Reductase Inhibitors) RN - 0 (Androgen Receptor Antagonists) RN - 0 (Androgens) RN - 0 (Androstenes) RN - 0 (Benzamides) RN - 0 (Chromatin) RN - 0 (Nitriles) RN - 0 (Receptors, Androgen) RN - 0 (delta4-abiraterone) RN - 08J2K08A3Y (Dihydrotestosterone) RN - 2010-15-3 (Phenylthiohydantoin) RN - 93T0T9GKNU (enzalutamide) RN - EC 1.1.- (3-Hydroxysteroid Dehydrogenases) RN - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase) RN - EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase) RN - G819A456D0 (abiraterone) SB - IM CIN - Nat Rev Urol. 2015 Jul;12(7):363. PMID: 26032546 CIN - Cell Cycle. 2015;14(20):3213-4. PMID: 26313523 CIN - Cancer Biol Ther. 2016 Apr 2;17 (4):337-8. PMID: 26828765 MH - 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors/metabolism MH - 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/metabolism MH - 5-alpha Reductase Inhibitors/metabolism/pharmacology/therapeutic use MH - Androgen Receptor Antagonists/metabolism/pharmacology/therapeutic use MH - Androgens/biosynthesis/metabolism MH - Androstenes/chemistry/*metabolism/*pharmacology/therapeutic use MH - Animals MH - Benzamides MH - Biosynthetic Pathways/drug effects MH - Biotransformation MH - Cell Division MH - Chromatin/metabolism MH - Dihydrotestosterone/metabolism MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Male MH - Mice MH - Nitriles MH - Phenylthiohydantoin/analogs & derivatives/pharmacology MH - Prostatic Neoplasms/*drug therapy/enzymology/*metabolism/pathology MH - Prostatic Neoplasms, Castration-Resistant/drug therapy MH - Receptors, Androgen/metabolism MH - Steroid 17-alpha-Hydroxylase/antagonists & inhibitors/metabolism MH - Survival Analysis MH - Xenograft Model Antitumor Assays PMC - PMC4506215 MID - NIHMS671246 EDAT- 2015/06/02 06:00 MHDA- 2016/03/02 06:00 PMCR- 2016/01/16 CRDT- 2015/06/02 06:00 PHST- 2014/10/01 00:00 [received] PHST- 2015/03/10 00:00 [accepted] PHST- 2015/06/02 06:00 [entrez] PHST- 2015/06/02 06:00 [pubmed] PHST- 2016/03/02 06:00 [medline] PHST- 2016/01/16 00:00 [pmc-release] AID - nature14406 [pii] AID - 10.1038/nature14406 [doi] PST - ppublish SO - Nature. 2015 Jul 16;523(7560):347-51. doi: 10.1038/nature14406. Epub 2015 Jun 1.