title: Reduction of prostate cancer incidence by naftopidil, an α1 -adrenoceptor antagonist and transforming growth factor-β signaling inhibitor.
abstract: OBJECTIVE
  Quinazoline-based α(1) -adrenoceptor antagonists are known to inhibit prostate tumor growth through induction of apoptosis. We investigated the effect of a naphthalene-based α(1) -adrenoceptor antagonist, naftopidil, on prostate cancer incidence, apoptosis of prostatic cell and transforming growth factor-β signaling.
  
  
  METHODS
  Prescription records were linked to pathological data for men who continued naftopidil (n = 766) or tamsulosin (n = 1015) for 3 months or longer between 2003 and 2010. Prostate cancer incidence was analyzed by log-rank test and the Cox proportional hazards model. Apoptosis and cell cycle arrest in human tissues were assessed by immunohistochemical detection of Bcl2 and p21, respectively. Growth inhibition and apoptosis treatment with naftopidil and tamsulosin were assessed in cancer cell lines. Interference with transforming growth factor-β signaling was examined by western blot analysis.
  
  
  RESULTS
  Prostate cancer incidence was significantly lower in men who received naftopidil for 3 months or longer compared with tamsulosin (P = 0.035). Multivariate analysis confirmed a decreased hazard ratio, 0.46, for naftopidil use (P = 0.013), which was more evident with longer treatment. Immunohistochemical positivity for Bcl2, a marker for resistance to apoptosis, was less frequently detected in prostate cancer cells of men who received naftopidil compared with tamsulosin (P < 0.05). Naftopidil inhibited cancer cell growth, induced apoptosis and blocked Smad2 phosphorylation activated by transforming growth factor-β in cell lines, with a half maximal inhibitory concentration of 1.1 µmol/L.
  
  
  CONCLUSIONS
  Naftopidil seems to reduce prostate cancer incidence, possibly by inducing apoptosis, preferentially in cancer cells, and blocking transforming growth factor-β signaling.
authors.affiliation: Department of Urology, The University of Tokyo Hospital, Tokyo, Japan; Department of Urology, The Fraternity Memorial Hospital, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kumano
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirano
authors.forename: Motofumi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuhara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Enomoto
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000453:epidemiology*; D012189:Retrospective Studies; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077409:Tamsulosin; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D009281:Naphthalenes; D010879:Piperazines; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D000077409:Tamsulosin; C064357:naftopidil
keywords: adrenoceptor; incidence; naftopidil; prostate cancer; transforming growth factor