Dihydrotestosterone synthesis pathways from inactive androgen 5alpha-androstane-3beta,17beta-diol in prostate cancer cells: Inhibition of intratumoural 3beta-hydroxysteroid dehydrogenase activities by abiraterone.

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Ando T, Nishiyama T, Takizawa I, Ishizaki F, Miyashiro Y, Takeda K, Hara N, Tomita Y

Sci Rep. 2016 Aug 26;6:32198. doi: 10.1038/srep32198.

PubMed ID

27561382 [ View in PubMed

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Abstract

Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5alpha-androstane-3beta,17beta-diol (3beta-diol), which is inactive androgen metabolized from DHT. 3beta-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3beta-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Delta5-androstenediol but also converted directly to DHT which is the main pathway from 3beta-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3beta-diol, by the inhibition of the intratumoural 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3beta-diol to DHT was catalysed by 3beta-HSD and abiraterone could inhibit this activity of 3beta-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3beta-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3beta-HSD activity could be a new approach to castration-resistant prostate cancer treatment.

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Testosterone undecanoate DB13946 Testosterone DB00624 Undecanoate DBMET03460	Details