Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis

Sameer S Udhane; Bernhard Dick; Qingzhong Hu; Rolf W Hartmann; Amit V Pandey

doi:10.1016/j.bbrc.2016.07.019

Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis

Biochem Biophys Res Commun. 2016 Sep 2;477(4):1005-1010. doi: 10.1016/j.bbrc.2016.07.019. Epub 2016 Jul 6.

Authors

Sameer S Udhane¹, Bernhard Dick², Qingzhong Hu³, Rolf W Hartmann⁴, Amit V Pandey⁵

Affiliations

¹ Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, University Children's Hospital Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
² Department of Clinical Research, University of Bern, 3010 Bern, Switzerland; Department of Nephrology, Hypertension and Clinical Pharmacology, University Hospital of Bern, Bern, Switzerland.
³ Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, Saarbrücken, Germany.
⁴ Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E 8.1, 66123 Saarbrücken, Germany.
⁵ Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, University Children's Hospital Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland. Electronic address: amit@pandeylab.org.

PMID: 27395338
DOI: 10.1016/j.bbrc.2016.07.019

Abstract

The orteronel, abiraterone and galeterone, which were developed to treat castration resistant prostate cancer, inhibit 17,20 lyase activity but little is known about their effects on adrenal androgen biosynthesis. We studied the effect of several inhibitors and found that orteronel was selective towards 17,20 lyase activity than abiraterone and galeterone. Gene expression analysis showed that galeterone altered the expression of HSD3B2 but orteronel did not change the expression of HSD3B2, CYP17A1 and AKR1C3. The CYP19A1 activity was not inhibited except by compound IV which lowered activity by 23%. Surprisingly abiraterone caused complete blockade of CYP21A2 activity. Analysis of steroid metabolome by gas chromatography - mass spectrometry revealed changes in steroid levels caused by different inhibitors. We can conclude that orteronel is a highly specific inhibitor of 17,20 lyase activity. The discovery of these specific drug actions on steroidogenic enzyme activities would be valuable for understanding the regulation of androgens.

Keywords: Abiraterone; CYP17A1; CYP21A2; Castration resistant prostate cancer; Orteronel; PCOS; Premature adrenarche.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Glands / cytology
Adrenal Glands / drug effects
Adrenal Glands / metabolism*
Androgens / biosynthesis*
Androstadienes / administration & dosage
Androstenes / administration & dosage
Antineoplastic Agents / administration & dosage*
Benzimidazoles / administration & dosage
Cell Line
Dose-Response Relationship, Drug
Humans
Imidazoles / administration & dosage
Male
Naphthalenes / administration & dosage
Prostatic Neoplasms / drug therapy*
Steroid 17-alpha-Hydroxylase / antagonists & inhibitors*

Substances

Androgens
Androstadienes
Androstenes
Antineoplastic Agents
Benzimidazoles
Imidazoles
Naphthalenes
CYP17A1 protein, human
Steroid 17-alpha-Hydroxylase
abiraterone
orteronel
3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene