title: Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma.
abstract: OBJECTIVE
  Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment.
  
  
  METHODS
  MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells.
  
  
  RESULTS
  EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells.
  
  
  CONCLUSIONS
  The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagaya
authors.forename: Kozo
authors.initials: K
authors.lastname: Kuribayashi
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: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D058892:Adenosine Deaminase Inhibitors; D009025:Morpholines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C416933:ABT 702; C010192:9-(2-hydroxy-3-nonyl)adenine; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine