title: Antitumor activity of MEK and PI3K inhibitors against malignant pleural             mesothelioma cells in vitro and in vivo.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive malignancy for which there is no approved targeted therapy. We examined the therapeutic efficacy of the mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors against human MPM cell lines both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. In addition, the molecular mechanisms of these agents were confirmed in vitro and in vivo. The MEK or the PI3K inhibitor suppressed MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. In addition, combined use of the MEK and PI3K inhibitors showed an additive or synergistic inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with MEK or PI3K inhibitor suppressed the production of thoracic tumors and pleural effusion and prolonged the survival time of EHMES-10 cell-bearing SCID mice. The combination therapy more effectively prolonged the survival time compared to treatment with either individual drug. Immunohistochemical and western blot analysis of thoracic tumors suggested that these agents induced cell cycle arrest, apoptosis and inhibition of tumor angiogenesis. Our results suggest that a combination of MEK and PI3K inhibitors is a promising therapeutic strategy for MPM.
authors.affiliation: Department of Integrated Medicine and Informatics, Ehime University                     Graduate School of Medicine, Ehime, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hamada
authors.forename: Naohiko
authors.initials: N
authors.lastname: Hamaguchi
authors.forename: Aki
authors.initials: A
authors.lastname: Kato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katayama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Irifune
authors.forename: Ryoji
authors.initials: R
authors.lastname: Ito
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okura
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one