title: Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285-94. ©2016 AACR.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takayama
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan. nhattori@hiroshima-u.ac.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Omori
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Akita
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008654:Mesothelioma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000086002:Mesothelioma, Malignant; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry* / Q000378:metabolism; D010997:Pleural Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D014408:Biomarkers, Tumor; D003998:Dicarboxylic Acids; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C000589255:SK-216; D002945:Cisplatin