Molecular Chemoprevention and Therapeutics The Hormel Institute, University of Minnesota, 801, 16th Ave NE, AUSTIN, MN, 55912, United States.
Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify agents those could target AR for both disease types. We provide mechanism-based evidence that Lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of AR in vitro and in vivo.
Normal prostate epithelial cell (RWPE-1), LAPC4 (wild-functional AR/ADPC), LNCaP (mutant-functional/AR/ADPC) and C4-2b (mutant-functional/AR/CRPC) cells were used to test the anti-AR activity of Lupeol. Cells grown under androgen-rich environment and treated with Lupeol were tested for proliferation, AR-transcriptional activity, AR competitive ligand-binding, AR-DNA-binding and AR-ARE/target gene binding. Further, in silico molecular modeling for Lupeol-AR binding was performed. Athymic mice bearing C4-2b and LNCaP cell-originated tumors were treated intra-peritoneally with Lupeol (40 mg/kg; 3-times/week) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, Lupeol-serum levels were measured.
Lupeol significantly inhibited R1881 (androgen-analogue)-induced (1) transcriptional activity of AR and (2) expression of PSA. Lupeol (1) competed antagonistically with androgen for AR, (2) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK and IL-6, and (3) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to anti-hormone therapy. HPLC analysis showed that Lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels.
Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP.
Written by:
Siddique HR, Mishra SK, Karnes RJ, Saleem M. Are you the author?
Reference: Clin Cancer Res. 2011 Jun 28. Epub ahead of print.
doi: 10.1158/1078-0432.CCR-11-0916
PubMed Abstract
PMID: 21712449
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