Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade
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Michael V. Fiandalo1, John J. Stocking1, Elena A. Pop1, John H. Wilton1,2, Krystin M. Mantione2, Yun Li1, Kristopher M. Attwood3, Gissou Azabdaftari4, Yue Wu1, David S. Watt5, Elizabeth M. Wilson6 and James L. Mohler1
1Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
2Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
3Department of Biostatistics and Bioinformatics Roswell Park Cancer Institute, Buffalo, NY 14263, USA
4Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
5Center for Pharmaceutical Research and Innovation and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
6Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA
James L. Mohler, email: [email protected]
Keywords: androstanediol; dihydrotestosterone; dutasteride; 3α-oxidoreductases; androgen deprivation therapy
Received: September 06, 2017 Accepted: November 19, 2017 Published: January 10, 2018
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.
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