2. Academic Validation
  3. Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade

Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade

  • Oncotarget. 2018 Jan 10;9(13):11227-11242. doi: 10.18632/oncotarget.24107.
Michael V Fiandalo 1,  John J Stocking 1,  Elena A Pop 1,  John H Wilton 1 2,  Krystin M Mantione 2,  Yun Li 1,  Kristopher M Attwood 3,  Gissou Azabdaftari 4,  Yue Wu 1,  David S Watt 5,  Elizabeth M Wilson 6,  James L Mohler 1
Affiliations

Affiliations

  • 1 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
  • 2 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
  • 3 Department of Biostatistics and Bioinformatics Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
  • 4 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
  • 5 Center for Pharmaceutical Research and Innovation and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
  • 6 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
PMID: 29541409 DOI: 10.18632/oncotarget.24107
Abstract

Androgen deprivation therapy (ADT) is palliative and prostate Cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.

Keywords

3α-oxidoreductases; androgen deprivation therapy; androstanediol; dihydrotestosterone; dutasteride.

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