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.
| Original language | English |
|---|---|
| Pages (from-to) | 11227-11242 |
| Number of pages | 16 |
| Journal | Oncotarget |
| Volume | 9 |
| Issue number | 13 |
| DOIs | |
| State | Published - 2018 |
Bibliographical note
Publisher Copyright:© Fiandalo et al.
Funding
James L. Mohler: P01-CA77739, DoD Prostate Cancer Research Program Award No. W81XWH-16-1-0635; Michael V. Fiandalo: Postdoctoral 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.
| Funders | Funder number |
|---|---|
| National Childhood Cancer Registry – National Cancer Institute | P30-CA016056, P20-RR020171 |
Keywords
- 3a-oxidoreductases
- Androgen deprivation therapy
- Androstanediol
- Dihydrotestosterone
- Dutasteride
ASJC Scopus subject areas
- Oncology
