title: Naftopidil induces apoptosis in malignant mesothelioma cell lines independently of α1-adrenoceptor blocking.
abstract: BACKGROUND
  Naftopidil, an α1-adrenoceptor blocker, has been clinically used for the treatment of benign prostate hyperplasia and hypertension. Emerging evidence has shown that naftopidil exhibits an antitumor effect on a variety of cancer types including prostate cancer. The aim of the present study was to investigate naftopidil-induced apoptosis in human malignant mesothelioma cells and to shed light on the underlying mechanism.
  
  
  METHODS
  3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, western blotting, and enzymatic assay of caspase-3, -8, and -9 activities were carried out on human malignant mesothelioma cell lines NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells. To knock-down α1D-adrenoceptor, siRNA to silence human α1D-adrenoceptor-targeted gene was constructed and transfected into cells.
  
  
  RESULTS
  Naftopidil induced apoptosis in all the investigated malignant mesothelioma cells, and a similar effect was obtained with prazosin, another α1-adrenoceptor blocker. α1-Adrenoceptor is linked to Gq/11 protein involving activation of protein kinase C (PKC). Naftopidil-induced reduction in cell viability was inhibited by GF109203X, while prazosin-induced in cell viability was less affected. Knocking-down α1D-adrenoceptor promoted malignant mesothelioma cell proliferation. Both naftopidil and prazosin activated caspase-3 and -8 in all the investigated malignant mesothelioma cells.
  
  
  CONCLUSIONS
  Naftopidil, as well as prazosin, has the potential to induce apoptosis in malignant mesothelioma cells by activating caspase-8 and the effector caspase-3, regardless of α1-adrenoceptor blocking.
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Masachika
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Akinobu
authors.initials: A
authors.lastname: Gotoh
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000970:Antineoplastic Agents; D009281:Naphthalenes; D010879:Piperazines; D020169:Caspases; C064357:naftopidil