title: Piperazine-based Alpha-1 AR Blocker, Naftopidil, Selectively Suppresses Malignant Human Bladder Cells via Induction of Apoptosis.
abstract: A retrospective observational cohort study has shown that exposure to alpha-1 adrenergic receptor (AR) blocker reduces the risk of bladder cancer (BCa). We investigated the antitumor activity of alpha-1 blockers, that are administered long-term therapeutically, in BCa. The antitumor activity of alpha-1 blockers was evaluated in terms of cell viability, cell cycle, competition, and apoptotic signaling in BCa cells. Our cell viability studies showed that naftopidil was one of the strongest alpha-1 AR blockers, regarding its antitumor action in BCa cells, independent of the grade of malignancy, but with no similar action on normal human bladder cells. Oral administration of naftopidil reduced tumor volume in a xenograft model. Our own competitive analysis using an alpha-1 AR agonist and other alpha-1 AR blockers showed that naftopidil activated cell death signaling without inhibitory action on alpha-1 ARs. We conclude that naftopidil has potential as an antitumor drug against BCa in vitro and in vivo. This finding provides a rationale for developing naftopidil in grade-independent treatment of BCa.
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan Department of Bioscience, Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo, Japan.
authors.forename: Yusuke U
authors.initials: YU
authors.lastname: Nakagawa
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Nagaya
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan cellgene@hyo-med.ac.jp.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Gotoh
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000317:Adrenergic alpha-Antagonists; D000970:Antineoplastic Agents; D009281:Naphthalenes; D010879:Piperazines; C064357:naftopidil
keywords: Bladder cancer; alpha-1 AR blocker; drug repositioning; naftopidil; toxicity