Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells

Abstract

Malignant mesothelioma (MM) is an aggressive malignant neoplasm which rapidly invades pleural tissues and has a poor prognosis. Here, we explore enhancement of the effect of irinotecan [camptothecin-11 (CPT-11)] by the p53-dependent induction of carboxylesterase 2 (CES2), a CPT-11-activating enzyme, in MM. The level of CES2 mRNA was greatly increased on treatment with nutlin-3a. A combination of CPT-11 and nutlin-3a inhibited the growth of MM cells more effectively than either drug alone. Knocking down CES2 in MM cells reduced the effect of the drug combination, and its forced expression in MESO4 cells enhanced the growth inhibitory activity of CPT-11 in the absence of nutlin-3a. Enhancement of the growth inhibitory activity of CPT-11 by nutlin-3a suggests a possible new combinatorial MM chemotherapy regimen. Malignant mesotheliomas (MMs) are rare fatal malignancies associated with the exposure to asbestos, con-stituting~0.2% of all newly diagnosed malignancies [1]. MMs originate from mesothelial cells and fall into three main subtypes, epithelioid, sarcomatoid, and biphasic, according to the histological phenotype [2]. MMs of the sarcomatoid subtype have an exceptionally poor prognosis [3]. Most MM patients have unresectable disease, and therefore, different anticancer drug regimens have been tested in clinical trials.