title: Carbidopa enhances antitumoral activity of bicalutamide on the androgen receptor-axis in castration-resistant prostate tumors.
abstract: BACKGROUND
  Response to bicalutamide after castration failure is not durable and treatment options at this stage are limited. Carbidopa, an L-dopa decarboxylase (AR-coactivator) inhibitor, has been shown to retard prostate tumor growth/PSA production in xenografts. Here, we hypothesize that pharmacological targeting of the AR-axis by combination treatment with bicalutamide plus carbidopa significantly enhances antitumoral activity in vitro and in vivo compared to monotherapy with either drug.
  
  
  METHODS
  Carbidopa was tested for its ability to enhance the effects of bicalutamide on cell viability, apoptosis and PSA transactivation in LNCaP and C4-2 cells. The castration-resistant prostate cancer (CRPC) LNCaP xenograft tumor model was used in vivo. After CRPC progression, mice were treated with carbidopa (50 mg/kg) and bicalutamide (50 mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly.
  
  
  RESULTS
  Combination treatment of carbidopa plus bicalutamide significantly inhibited cell viability in both cell lines and induced apoptosis. The combination treatment also decreased androgen-induced PSA transactivation by 62.6% in LNCaP cells and by 55.6% in C4-2 cells compared to control, while bicalutamide monotherapy reduced PSA levels by 27.5% and 29.1% in LNCaP and C4-2 cells. In vivo, bicalutamide monotherapy delayed LNCaP CRPC tumor growth rate by 72.2%, while combination treatment reduced tumor growth by 84.4% compared to control. Serum PSA was also reduced 70.6% with bicalutamide monotherapy, while combination therapy reduced PSA levels by 76.7% compared to control.
  
  
  CONCLUSIONS
  This study demonstrates preclinical proof-of-principle that pharmacological targeting of prostate tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays CRPC tumor progression in vivo.
authors.affiliation: The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.forename: Latif A
authors.initials: LA
authors.lastname: Wafa
authors.forename: Francois
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Helen
authors.initials: H
authors.lastname: Cheng
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D015259:Dopamine Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D002230:Carbidopa