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Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma
Objectives 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 w...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068714/ https://www.ncbi.nlm.nih.gov/pubmed/33300108 http://dx.doi.org/10.1007/s10637-020-01040-y |
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author | Dell’Anno, Irene Martin, Sarah A. Barbarino, Marcella Melani, Alessandra Silvestri, Roberto Bottaro, Maria Paolicchi, Elisa Corrado, Alda Cipollini, Monica Melaiu, Ombretta Giordano, Antonio Luzzi, Luca Gemignani, Federica Landi, Stefano |
author_facet | Dell’Anno, Irene Martin, Sarah A. Barbarino, Marcella Melani, Alessandra Silvestri, Roberto Bottaro, Maria Paolicchi, Elisa Corrado, Alda Cipollini, Monica Melaiu, Ombretta Giordano, Antonio Luzzi, Luca Gemignani, Federica Landi, Stefano |
author_sort | Dell’Anno, Irene |
collection | PubMed |
description | Objectives 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-020-01040-y. |
format | Online Article Text |
id | pubmed-8068714 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-80687142021-05-05 Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma Dell’Anno, Irene Martin, Sarah A. Barbarino, Marcella Melani, Alessandra Silvestri, Roberto Bottaro, Maria Paolicchi, Elisa Corrado, Alda Cipollini, Monica Melaiu, Ombretta Giordano, Antonio Luzzi, Luca Gemignani, Federica Landi, Stefano Invest New Drugs Preclinical Studies Objectives 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-020-01040-y. Springer US 2020-12-09 2021 /pmc/articles/PMC8068714/ /pubmed/33300108 http://dx.doi.org/10.1007/s10637-020-01040-y Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Preclinical Studies Dell’Anno, Irene Martin, Sarah A. Barbarino, Marcella Melani, Alessandra Silvestri, Roberto Bottaro, Maria Paolicchi, Elisa Corrado, Alda Cipollini, Monica Melaiu, Ombretta Giordano, Antonio Luzzi, Luca Gemignani, Federica Landi, Stefano Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
title | Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
title_full | Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
title_fullStr | Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
title_full_unstemmed | Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
title_short | Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
title_sort | drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma |
topic | Preclinical Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068714/ https://www.ncbi.nlm.nih.gov/pubmed/33300108 http://dx.doi.org/10.1007/s10637-020-01040-y |
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