Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo.

International Journal of Oncology
Seigo MiyoshiJitsuo Higaki

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 angioge...Continue Reading

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Citations

Aug 21, 2013·Journal of Cellular Biochemistry·Joyce K ThompsonArti Shukla
Apr 26, 2014·British Journal of Cancer·S ZhouW-B Ou
Sep 21, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sara A FlaniganStephen Leong

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Methods Mentioned

BETA
ELISA
Protein Assay

Software Mentioned

CalcuSyn
ModFitLT

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