Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma

Our plain-English summary of Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma, by M.L. Hartman, J.M. Esposito, B.Y. Yeap, et al (The Journal of Thoracic and Cardiovascular Surgery, 2010).

The study

• Authors: M.L. Hartman, J.M. Esposito, B.Y. Yeap, D.J. Sugarbaker
• Journal: The Journal of Thoracic and Cardiovascular Surgery
• Published: 2010;139(5):1233-40
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objective: Although platinum-based chemotherapy is widely used in malignant pleural mesothelioma, its modest therapeutic effect warrants identification of enhancing agents. As with many cancers, the phosphatidylinositol 3-kinase/Akt pathway is often activated in malignant pleural mesothelioma and has been implicated in the tumor's aggressiveness. Sirolimus is a well-established inhibitor of the mammalian target of rapamycin. We sought to determine whether combination treatment with sirolimus and cisplatin would enhance cell death in malignant pleural mesothelioma.

Methods: Human malignant pleural mesothelioma cell lines were incubated with sirolimus or cisplatin alone or in combination and assayed for cell viability. To characterize phosphorylation status after treatment, Akt and downstream proteins of mammalian target of rapamycin pathway, p70 S6 kinase and 4E-BP1, were analyzed by Western blot. Effect of combination treatment was also analyzed with extreme drug resistance assay in 12 human malignant pleural mesothelioma tumors with varying resistance to cisplatin.

Results: Individual malignant pleural mesothelioma cell lines exhibited a range of sensitivities to each drug without correlation with subtype. Sirolimus and cisplatin significantly (P = .029) increased cell death versus either drug alone in 4 cell lines. Combined treatment caused dephosphorylation of Akt, 4E-BP1, and p70 S6 kinase. Cell proliferation was significantly decreased in tumors subjected to sirolimus and cisplatin versus cisplatin or sirolimus alone.

Conclusions: Sirolimus appears to enhance the cytotoxicity of cisplatin in malignant pleural mesothelioma cell lines through the mammalian target of rapamycin pathway. These results provide a basis for the clinical evaluation of combined sirolimus and cisplatin chemotherapy in malignant pleural mesothelioma.

2010. Published by Mosby, Inc.

In plain English

This laboratory study tested whether adding sirolimus, a drug that blocks a cell-growth protein called mTOR, to the chemotherapy drug cisplatin killed more malignant pleural mesothelioma cells than either drug alone. It did not study asbestos exposure, and no patients were treated. The authors used six human mesothelioma cell lines grown in the laboratory and 12 tumor specimens removed during surgery. The cell lines varied in how sensitive they were to each drug, and this was not linked to tumor subtype. In four cell lines (MS589, MS428, JMN1B and MS924), combined treatment increased loss of cell viability compared with cisplatin alone. In two others (MS257 and H2052), the difference from cisplatin alone was not statistically significant. In two cell lines, the combination reduced phosphorylation (a chemical tag linked to activity) of Akt, p70 S6 kinase and 4E-BP1, which are proteins in the mTOR pathway. In the 12 tumor specimens, average growth inhibition was 84% with the combination, compared with 61% for cisplatin alone and 64% for sirolimus alone. The authors called the tumor results preliminary. They concluded that sirolimus appears to enhance cisplatin's effect through the mTOR pathway, and that this supports clinical testing.

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 (in vitro) drug study on human mesothelioma cell lines, plus a cellular proliferation (extreme drug resistance) assay on surgical tumor specimens
• Who was studied: 6 human malignant pleural mesothelioma cell lines from Brigham and Women's Hospital, Boston: MS257, MS924, H2052 and JMN1B (epithelial), MS428 (sarcomatoid) and MS589 (biphasic). Also 12 tumor specimens removed during cytoreductive surgery for malignant pleural mesothelioma.
• Exposure: Not asbestos. Cells were exposed to the drugs sirolimus (1 to 500 nmol/L, combination dose 100 nmol/L) and cisplatin (combination dose 50, printed as mmol/L), alone or together, for 24 hours before the drugs were washed out.
• Main results:
  • Combined sirolimus and cisplatin increased cell death compared with either drug alone in 4 cell lines. Combined treatment caused dephosphorylation of Akt, 4E-BP1 and p70 S6 kinase.
  • Comparing combined treatment with cisplatin alone 48 hours after drug washout, the article reports figures of 91.2% (P less than .0001) for MS589 and 45.1% (P = .0002) for MS428 for loss of cell viability.
  • In the MS257 and H2052 cell lines, loss of cell viability with combined treatment did not reach statistical significance relative to cisplatin alone. These cell lines were relatively highly sensitive to cisplatin alone.
  • In the MS428 and H2052 cell lines, sirolimus alone increased Akt phosphorylation (activation). Cisplatin alone, or cisplatin combined with sirolimus, dephosphorylated Akt.
  • Both cell lines showed moderate dephosphorylation of 4E-BP1 at Thr 70 with either drug alone, and virtually complete dephosphorylation with the combination.
  • In the 12 tumor specimens, average percent growth inhibition was 61% (range 34% to 87%) with cisplatin alone and 84% (range 68% to 98%) with the combination. The average increase with the combination was 23% (range 2% to 44%), P = .0002.
  • In the 12 tumor specimens, average percent growth inhibition was 64% (range 1% to 90%) with sirolimus alone and 84% (range 68% to 98%) with the combination. The average increase with the combination was 20% (range 6% to 74%), P = .0133.
• The authors' conclusion: The authors concluded that sirolimus appears to enhance the cell-killing effect of cisplatin in malignant pleural mesothelioma cell lines through the mTOR pathway, and that the results provide a basis for clinical evaluation of the combination.
• Limitations the authors state:
  • The authors described the tumor specimen results as preliminary.
  • The authors could not reliably calculate IC50 values for the more cisplatin-resistant cell lines (MS924 and MS428).
  • The authors stated that further investigation is needed to identify other pathways involved in how the drug combination works.

Topics

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

Medical terms in this study, explained in our Lexicon: Cisplatin, Mesothelioma, Chemotherapy, Pleural Mesothelioma.

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