Open Access

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

  • Authors:
    • Seigo Miyoshi
    • Hironobu Hamada
    • Naohiko Hamaguchi
    • Aki Kato
    • Hitoshi Katayama
    • Kazunori Irifune
    • Ryoji Ito
    • Tatsuhiko Miyazaki
    • Takafumi Okura
    • Jitsuo Higaki
  • View Affiliations

  • Published online on: May 8, 2012     https://doi.org/10.3892/ijo.2012.1462
  • Pages: 449-456
  • Copyright: © Miyoshi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.
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August 2012
Volume 41 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Miyoshi S, Hamada H, Hamaguchi N, Kato A, Katayama H, Irifune K, Ito R, Miyazaki T, Okura T, Higaki J, Higaki J, et al: Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo. Int J Oncol 41: 449-456, 2012.
APA
Miyoshi, S., Hamada, H., Hamaguchi, N., Kato, A., Katayama, H., Irifune, K. ... Higaki, J. (2012). Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo. International Journal of Oncology, 41, 449-456. https://doi.org/10.3892/ijo.2012.1462
MLA
Miyoshi, S., Hamada, H., Hamaguchi, N., Kato, A., Katayama, H., Irifune, K., Ito, R., Miyazaki, T., Okura, T., Higaki, J."Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo". International Journal of Oncology 41.2 (2012): 449-456.
Chicago
Miyoshi, S., Hamada, H., Hamaguchi, N., Kato, A., Katayama, H., Irifune, K., Ito, R., Miyazaki, T., Okura, T., Higaki, J."Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo". International Journal of Oncology 41, no. 2 (2012): 449-456. https://doi.org/10.3892/ijo.2012.1462