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.
Highlights
The research and development for releasing new chemical entities into the therapeutic market is a complex, time-consuming, and costly process
First-line chemotherapy for Malignant Pleural Mesothelioma (MPM) consists of a combination of cisplatin with either pemetrexed or raltitrexed, where cisplatin could be substituted with carboplatin in elderly patients [4, 5]
To identify compounds active against MPM cells, we carried out a drug repositioning screen of 1170 FDA-approved drugs, at the unique dose of 10 μM, on a panel of five MPM cell lines (Mero-14, Mero-25, IST-Mes2, NCI-H28, and MSTO-211H) and one non-malignant immortalized mesothelial cell line (MeT-5A)
Summary
The research and development for releasing new chemical entities into the therapeutic market is a complex, time-consuming, and costly process. As showed by Van der Velden and coworkers, this type of approach could facilitate and accelerate the translation of existing drugs into the clinical use as novel anticancer agents [1]. A DR approach could help to provide a better therapeutic strategy for MPM patients, which is supported by the recent repurposing of the pyrvinium, pamoate [8]. To this end, in the present work we carried out a study where 1170 FDA-approved drugs were assayed for their cytotoxic effects on a panel of MPM cell lines
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