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

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. (J Thorac Cardiovasc Surg 2010; 139: 1233-40)