title: Carbidopa abrogates L-dopa decarboxylase coactivation of the androgen receptor and delays prostate tumor progression.
abstract: The androgen receptor (AR) plays a central role in prostate cancer progression to the castration-resistant (CR) lethal state. L-Dopa decarboxylase (DDC) is an AR coactivator that increases in expression with disease progression and is coexpressed with the receptor in prostate adenocarcinoma cells, where it may enhance AR activity. Here, we hypothesize that the DDC enzymatic inhibitor, carbidopa, can suppress DDC-coactivation of AR and retard prostate tumor growth. Treating LNCaP prostate cancer cells with carbidopa in transcriptional assays suppressed the enhanced AR transactivation seen with DDC overexpression and decreased prostate-specific antigen (PSA) mRNA levels. Carbidopa dose-dependently inhibited cell growth and decreased survival in LNCaP cell proliferation and apoptosis assays. The inhibitory effect of carbidopa on DDC-coactivation of AR and cell growth/survival was also observed in PC3 prostate cancer cells (stably expressing AR). In vivo studies demonstrated that serum PSA velocity and tumor growth rates elevated ∼2-fold in LNCaP xenografts, inducibly overexpressing DDC, were reverted to control levels with carbidopa administration. In castrated mice, treating LNCaP tumors, expressing endogenous DDC, with carbidopa delayed progression to the CR state from 6 to 10 weeks, while serum PSA and tumor growth decreased 4.3-fold and 5.4-fold, respectively. Our study is a first time demonstration that carbidopa can abrogate DDC-coactivation of AR in prostate cancer cells and tumors, decrease serum PSA, reduce tumor growth and delay CR progression. Since carbidopa is clinically approved, it may be readily used as a novel therapeutic strategy to suppress aberrant AR activity and delay prostate cancer progression.
authors.affiliation: Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Latif A
authors.initials: LA
authors.lastname: Wafa
authors.forename: Helen
authors.initials: H
authors.lastname: Cheng
authors.forename: Nathan
authors.initials: N
authors.lastname: Plaa
authors.forename: Fariba
authors.initials: F
authors.lastname: Ghaidi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukumoto
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004296:Dopa Decarboxylase / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen; D004296:Dopa Decarboxylase; D002230:Carbidopa