Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma

Abstract

SummaryObjectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future “drug repositioning” approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma

“…Our first strategy was aimed at selecting the set of molecules showing the highest activity on MPM cells, sparing the MeT-5A cell line. Thus, we found fludarabine and risedronic acid to be the most interesting molecules, as already reported [15]. However, we are aware that MeT-5A cells could not be the most appropriate model of non-malignant mesothelial cells.…”

“…The non-malignant cell lines were MeT-5A and LP-9. The specific information on these cells can be found in the previous work [15]. However, here we extended the assays also on Mero-95, ZL55, and MMP4.…”

“…All the materials and methods have been published in detail on a previous manuscript [15]. Here, we report only a brief description, highlighting the main differences.…”

“…The FDA-approved drug library was composed of 1170 entities (Selleck Chemicals, Houston, TX, USA) [15]. Cell viability was assessed through the use of CellTiter-Glo ® Luminescent Cell Viability Assay (Promega, Madison, WI, USA).…”

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…In a recent work Dell’Anno et al. have used a drug repositioning approach to screen five MPM cell lines with 1170 FDA-approved drugs ( 136 ). They identified fludarabine (F-araA) and risedronic acid (RIS) as effective in MPM through a mechanism of inhibition of STAT1 expression and nucleic acids synthesis.…”