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

// 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 and James L. Mohler 1 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 Correspondence to: James L. Mohler, email: James.Mohler@RoswellPark.org Keywords: androstanediol; dihydrotestosterone; dutasteride; 3α-oxidoreductases; androgen deprivation therapy Received: September 06, 2017      Accepted: November 19, 2017      Published: January 10, 2018 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.