Abstract | BACKGROUND: METHODS: RESULTS:
EB1089 induced significant expression of genes involved in androgen metabolism in prostate cancer cells. Real-Time PCR analysis revealed that VDR mediated significant regulation of CYP3A4, CYP3A5, CYP3A43, AKR1C1-3, UGT2B15/17, and HSD17B2. Data revealed potent regulation of CYP3A4 at the level of mRNA, protein expression and enzymatic activity, with VDR identified as the predominant regulator. Inhibition of CYP3A activity using the specific inhibitor ritonavir resulted in alleviation of the anti-proliferative response of VDR ligands in prostate cancer cells. Mass spectrometry revealed that overexpression of CYP3A protein in prostate cancer cells resulted in a significant increase in the oxidative inactivation of testosterone and DHEA to their 6-β-hydroxy-testosterone and 16-α-hydroxy-DHEA metabolites, respectively. CONCLUSIONS: These data highlight a potential application of VDR-based therapies for the reduction of growth-promoting androgens within the tumor micro-environment.
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Authors | Declan Doherty, Scarlett Anne Dvorkin, Edna Patricia Rodriguez, Paul Daniel Thompson |
Journal | The Prostate
(Prostate)
Vol. 74
Issue 3
Pg. 273-85
(Feb 2014)
ISSN: 1097-0045 [Electronic] United States |
PMID | 24242708
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2013 Wiley Periodicals, Inc. |
Chemical References |
- Androgens
- Cytochrome P-450 CYP3A Inhibitors
- RNA, Messenger
- Receptors, Calcitriol
- Testosterone
- Dehydroepiandrosterone
- Cytochrome P-450 CYP3A
- Calcitriol
- Ritonavir
- seocalcitol
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Topics |
- Androgens
(genetics, metabolism)
- Calcitriol
(analogs & derivatives, pharmacology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cytochrome P-450 CYP3A
(analysis, genetics)
- Cytochrome P-450 CYP3A Inhibitors
- Dehydroepiandrosterone
(metabolism)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Male
- Prostate
(drug effects, metabolism)
- Prostatic Neoplasms
(metabolism)
- Prostatic Neoplasms, Castration-Resistant
(metabolism, prevention & control)
- RNA, Messenger
(analysis)
- Receptors, Calcitriol
(agonists, physiology)
- Ritonavir
(pharmacology)
- Testosterone
(metabolism)
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