606 CARBIDOPA ENHANCES ANTITUMORAL ACTIVITY OF BICALUTAMIDE ON THE ANDROGEN RECEPTOR-AXIS IN CASTRATION-RESISTANT PROSTATE TUMORS (2011)

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011606 CARBIDOPA ENHANCES ANTITUMORAL ACTIVITY OF BICALUTAMIDE ON THE ANDROGEN RECEPTOR-AXIS IN CASTRATION-RESISTANT PROSTATE TUMORS Christian Thomas, Latif Wafa, Francois Lamoureux, Paul S. Rennie, and Martin E. Gleave Christian ThomasChristian Thomas Vancouver, Canada , Latif WafaLatif Wafa Vancouver, Canada , Francois LamoureuxFrancois Lamoureux Vancouver, Canada , Paul S. RenniePaul S. Rennie Vancouver, Canada , and Martin E. GleaveMartin E. Gleave Vancouver, Canada View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1459AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The identification of novel agents or combination therapies for castration-resistant prostate cancer (CRPC) remains a major challenge in prostate cancer drug development. A long-lasting response to bicalutamide, currently standard treatment after castration failure, is limited by its partially agonistic effects. Carbidopa is a potent drug that inhibits coactivation function of the androgen-receptor (AR) coactivator protein, L-dopa decarboxylase, and has previously been shown to retard prostate tumor growth and PSA production in xenograft experiments. In the current study, we hypothesize that pharmacological targeting of the AR-axis by combination treatment of bicalutamide plus carbidopa significantly enhances the antitumoral activity in vitro and in vivo compared to single use of each drug. METHODS Carbidopa was tested for its ability to enhance the effects of bicalutamide in cell viability assays and PSA transactivation by luciferase assay in LNCaP and C4-2 cells. For in vivo xenograft studies, LNCaP cells were inoculated s.c. in athymic nude mice. Mice were castrated and after CRPC progression randomily assigned to treatments with carbidopa (50mg/kg) and bicalutamide (50mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly. RESULTS Combination treatment of carbidopa plus bicalutamide significantly inhibited cell growth for both LNCaP and C4-2 cells. More specifically, in LNCaP cells, bicalutamide mono treatment inhibited cell growth by 48%, while the combination treatment reduced cell growth by 62% compared to control. Similarly in C4-2 cells, bicalutamide mono and combination treatments inhibited cell growth by 49% and 68%, respectively. The combination treatment also decreased androgen-induced PSA transactivation by 75% in LNCaP cells and by 65% in C4-2 cells compared to control, while bicalutamide mono therapy only reduced PSA levels by 27% (LNCaP) and 29% (C4-2). In vivo, bicalutamide mono delayed the growth rate of LNCaP CRPC tumors by 3.2-fold, while combination treatment reduced tumor growth by 6.8-fold compared to control. Serum PSA production was also reduced 2.5-fold with bicalutamide mono treatment, while the combination therapy reduced PSA progression by 4.3-fold compared to control. CONCLUSIONS This study reports preclinical proof-of-principle that pharmacological targeting of CRPC tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays tumor progression in vivo. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e244 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.Metrics Author Information Christian Thomas Vancouver, Canada More articles by this author Latif Wafa Vancouver, Canada More articles by this author Francois Lamoureux Vancouver, Canada More articles by this author Paul S. Rennie Vancouver, Canada More articles by this author Martin E. Gleave Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...