Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer.

Abstract

Dehydroepiandrosterone (DHEA)-SO4 of adrenal origin is the major C19 steroid in the serum. It is a precursor of intratumoral androgen biosynthesis in patients with advanced prostate cancer following chemical or surgical castration. DHEA is a product of the P450c17 (17α-hydroxylase-17,20-lyase) enzyme. Despite inhibition of P450c17 with new agents, e.g., Abiraterone acetate, Orterenol, and Galeterone, the level of enzyme inhibition rarely exceeds 90% leaving behind a significant depot for androgen biosynthesis within the tumor. For DHEA-SO4 to be utilized there is uptake by organic anion transporter polypeptides, deconjugation catalyzed by steroid sulfatase, and adaptive upregulation of prostate steroidogenic enzymes that will convert DHEA into either testosterone or dihydrotestosterone. The depot of DHEA-SO4 that remains after P450c17 inhibition and the adaptive responses that occur within the tumor to promote DHEA utilization contribute to mechanisms of drug resistance observed with P450c17 inhibitors. Knowledge of these mechanisms identify new targets for therapeutics that could be used to surmount drug resistance in prostate cancer.

• Authors: Trevor M Penning
• Journal: Vitamins and hormones (Vitam Horm) Vol. 108 Pg. 309-331 ( 2018) ISSN: 0083-6729 [Print] United States
• PMID: 30029732 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)
• Copyright: © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Delayed-Action Preparations
• Dehydroepiandrosterone Sulfate
• CYP17A1 protein, human
• Steroid 17-alpha-Hydroxylase

Topics

• Antineoplastic Agents (pharmacology)
• Dehydroepiandrosterone Sulfate (administration & dosage, metabolism, therapeutic use)
• Delayed-Action Preparations
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors)