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.
Digital Object Identifier (DOI)
James L. Mohler: P01-CA77739, DoD Prostate Cancer Research Program Award No. W81XWH-16-1-0635; Michael V. Fiandalo: Post-doctoral Training Award W81XWH-15-1-0409; and, in part, by the NCI Cancer Center Support Grant to RPCI (P30-CA016056) for the Bioanalytics, Metabolomics and Pharmacokinetics, Pathology Network, Biostatistics and Bioinformatics and Genomics Shared Resources; David S. Watt: P20-RR020171.
Fiandalo, Michael V.; Stocking, John J.; Pop, Elena A.; Wilton, John H.; Mantione, Krystin M.; Li, Yun; Attwood, Kristopher M.; Azabdaftari, Gissou; Wu, Yue; Watt, David S.; Wilson, Elizabeth M.; and Mohler, James L., "Inhibition of Dihydrotestosterone Synthesis in Prostate Cancer by Combined Frontdoor and Backdoor Pathway Blockade" (2018). Center for Pharmaceutical Research and Innovation Faculty Publications. 3.