title: Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation.
abstract: OBJECTIVE
  Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are responsible for this continued activity, which influences the efficacy of prostate cancer treatment. We hypothesized that combining a 5α-reductase inhibitor and an antiandrogen would block intratumor androgen synthesis and androgen receptor protein activity. Thus, it would act synergistically to reduce tumor cell proliferation.
  
  
  METHODS
  The expression level of 5α-reductase and androgen receptor in endocrine therapy naïve prostate cancer and castration resistant prostate cancer tissues, and cell line models was determined by microarray and quantitative polymerase chain reaction analysis. Intracellular androgen was measured with radioimmunoassay. Tumor cell proliferation was determined using coloric MTT assay. The synergistic effects of combination treatments on tumor cell proliferation were calculated using the Chou-Talalay equation.
  
  
  RESULTS
  In all prostate cancer cases 5α-reductase-1 and 3 were up-regulated. Androgen receptor was up-regulated in metastatic prostate cancer and castration resistant prostate cancer cases. The 5α-reductase inhibitor dutasteride effectively decreased dihydrotestosterone production in prostate cancer and castration resistant prostate cancer cell lines. Furthermore, dutasteride combined with the novel antiandrogen enzalutamide synergistically suppressed endocrine therapy naïve prostate cancer and castration resistant prostate cancer cell proliferation.
  
  
  CONCLUSIONS
  In this study the combination of a 5α-reductase inhibitor and (novel) antiandrogens synergistically inhibited tumor cell proliferation. These findings support clinical studies of combinations of a 5α-reductase inhibitor and (novel) antiandrogens as first line treatment of prostate cancer and castration resistant prostate cancer.
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands; Department of Urology, Ciptomangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Indonesia.
authors.forename: Agus Rizal A H
authors.initials: AR
authors.lastname: Hamid
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Verhaegh
authors.affiliation: NovioGendix, Nijmegen, The Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Smit
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Cindy
authors.initials: C
authors.lastname: van Rijt-van de Westerlo
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Inna
authors.initials: I
authors.lastname: Armandari
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Brandt
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: John P M
authors.initials: JP
authors.lastname: Sedelaar
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. Electronic address: Jack.Schalken@radboudumc.nl.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D001378:Azasteroids / Q000494:pharmacology*; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000068538:Dutasteride; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D000068538:Dutasteride
keywords: MDV 3100; antineoplastic combined chemotherapy protocols; castration-resistant; dutasteride; prostatic neoplasms