title: Combination treatment with naftopidil increases the efficacy of radiotherapy in PC-3 human prostate cancer cells.
abstract: OBJECTIVE
  Clinically, radiotherapy (RT) often leads to the development of prostate cancer (PCa) resistance because of protective responses in cancer cells. One of the mechanisms includes the upregulation of RT-induced antioxidant enzymes. Thus, combination therapy with RT and certain pharmaceutical drugs targeting antioxidant enzymes may be ideal for increasing the efficacy of RT with minimum side effects. Naftopidil is a subtype-selective α1D-adrenoceptor antagonist used for the treatment of benign prostatic hyperplasia (BPH). In our drug repositioning study, naftopidil showed not only unique growth-inhibitory effects but also AKT phosphorylation-inhibitory effects in PC-3 human PCa cells. Here, we examined the efficacy of additive naftopidil treatment in combination with RT in PC-3 cells.
  
  
  METHODS
  The effects of combination therapy with RT plus naftopidil were analyzed using an animal model of PC-3 xenografts in BALB/c nude mice. The expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was evaluated by western blotting.
  
  
  RESULTS
  Combination therapy with RT plus naftopidil induced a more efficacious delay in PC-3 xenograft tumor growth as compared with monotherapy with naftopidil or RT. In PC-3 tumors, combination therapy with RT plus naftopidil suppressed the upregulation of RT-induced MnSOD expression. In vitro, neither AKT inhibitor IV nor naftopidil directly altered MnSOD expression. Upregulation of RT-induced MnSOD expression was markedly suppressed by combination treatment with RT plus AKT inhibitor IV or naftopidil.
  
  
  CONCLUSIONS
  These results suggest that additive naftopidil treatment in combination with RT may increase the efficacy of RT for the treatment of PCa.
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Miki
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kajiwara
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Arima
authors.affiliation: Department of Diagnostic Pathology, Kuwana City Medical Center, Kuwana, Mie, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. sugimura@clin.medic.mie-u.ac.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugimura
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009281:Naphthalenes / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009281:Naphthalenes; D010879:Piperazines; C064357:naftopidil
keywords: Antioxidant enzyme; Combination therapy; Naftopidil; Prostate cancer; Radiotherapy