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

Our plain-English summary of Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo, by S. Miyoshi, H. Hamada, N. Hamaguchi, et al (International Journal of Oncology, 2012).

The study

• Authors: S. Miyoshi, H. Hamada, N. Hamaguchi, A. Kato, H. Katayama, K. Irifune, R. Ito, T. Miyazaki, T. Okura, J. Higaki
• Journal: International Journal of Oncology
• Published: 2012;41(2):449-56
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study from Ehime University in Japan tested two experimental drugs against malignant pleural mesothelioma cells. It did not study asbestos exposure. The authors used two human mesothelioma cell lines (EHMES-10 and MSTO211H) and immune-deficient SCID mice injected in the chest with EHMES-10 cells. The drugs were U0126, which blocks a protein called MEK, and LY294002, which blocks a protein called PI3K, given alone or together. In cell cultures, each drug slowed cell growth more at higher doses. The combination had a nearly additive effect in EHMES-10 cells and a synergistic effect in MSTO211H cells. In mice, two U0126 doses (30 and 40 mg/kg), the highest LY294002 dose (50 mg/kg) and the combination each lengthened survival compared with control mice (P less than 0.01). The combination appeared to extend survival more than either drug alone, but this difference was not statistically significant. Treated mice had less tumor and less chest fluid on day 30. The authors reported no side effects. They concluded the combination "may represent a promising novel therapeutic strategy" for this cancer. It was not tested in people.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on human mesothelioma cell lines in culture (in vitro) and in mice (in vivo)
• Who was studied: Two human malignant pleural mesothelioma cell lines. EHMES-10 came from the pleural effusion of a patient at the authors' institution, and MSTO211H was purchased from the American Type Culture Collection. The study also used male SCID mice aged six to eight weeks, inoculated in the thoracic cavity with EHMES-10 cells and randomized into eight groups of 7 mice.
• Exposure: No asbestos exposure was studied. The exposures were the MEK inhibitor U0126 (20 to 200 µM in cells; 20, 30 or 40 mg/kg in mice) and the PI3K inhibitor LY294002 (20 to 200 µM in cells; 12.5, 25 or 50 mg/kg in mice). A combination of 30 mg/kg U0126 and 25 mg/kg LY294002 was also tested. The drugs were given to the mice in the abdomen (intraperitoneally) twice a week.
• Main results:
  • In EHMES-10 cells, the concentrations that halved cell growth (IC50) were 66.8 µM for U0126 and 20.7 µM for LY294002
  • In MSTO211H cells, the IC50 values were 39.0 µM for U0126 and 29.9 µM for LY294002
  • Combined drug treatment gave an averaged combination index of 1.017 in EHMES-10 cells (nearly additive) and 0.54 in MSTO211H cells (synergistic)
  • In both cell lines, either drug given for 24 hours significantly increased the share of cells held in the G1 phase of the cell cycle compared with control (P less than 0.05)
  • In EHMES-10-bearing mice, U0126 at 30 or 40 mg/kg, LY294002 at 50 mg/kg, and the combination each significantly prolonged survival compared with the control group (P less than 0.01)
  • In mice, the combination prolonged survival more than either drug alone, but the difference was not statistically significant
  • In mice, the drugs alone or combined significantly reduced thoracic tumor growth and pleural effusion production compared with control (P less than 0.05)
  • Control mice had a median thoracic tumor weight of 487.7 mg (range 162.8 to 907.1) on day 30, with tumors in 5 of 5 mice and pleural effusion in 5 of 5
  • Mice given the combination had a median thoracic tumor weight of 7.5 mg (range 0 to 8.6) on day 30, with tumors in 3 of 5 mice and pleural effusion in 0 of 5
  • The authors reported no side effects, based on body weight, blood tests (total protein, BUN, creatinine, AST, ALT) and skin condition
• The authors' conclusion: The authors concluded that combining MEK and PI3K inhibitors may represent a promising new treatment strategy for malignant pleural mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Targeted Therapy, Apoptosis, Pleural Effusion, Angiogenesis.

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