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.
Document Type
Article
Publication Date
1-10-2018
Digital Object Identifier (DOI)
https://doi.org/10.18632/oncotarget.24107
Funding Information
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.
Repository Citation
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.
https://uknowledge.uky.edu/cpri_facpub/3
Notes/Citation Information
Published in Oncotarget, v. 9, no. 13, p. 11227-11242.
Copyright: Fiandalo et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.