A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma

Our plain-English summary of A Drug Screening Revealed Novel Potential Agents against Malignant Pleural Mesothelioma, by I. Dell'Anno, A. Melani, S.A. Martin, et al (Cancers, 2022).

The study

• Authors: I. Dell'Anno, A. Melani, S.A. Martin, M. Barbarino, R. Silvestri, M. Cipollini, A. Giordano, L. Mutti, A. Nicolini, L. Luzzi, R. Aiello, F. Gemignani, S. Landi
• Journal: Cancers
• Published: 2022;14(10)
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activation in all cancer lines tested. The proliferation was inhibited also on an extended panel of cell lines, including primary MPM cells. Thus, we suggest that cephalomannine, ouabain, thonzonium bromide, and emetine could represent novel candidates to be repurposed for improving the arsenal of therapeutic weapons in the fight against MPM.

In plain English

This was a laboratory study on cells, not patients. The authors re-examined their earlier screen of 1170 FDA-approved drugs, tested at 10 µM on one non-malignant (MeT-5A) and five malignant pleural mesothelioma (MPM) cell lines. It found 90 drugs toxic to at least four MPM lines. The authors then tested 38 drugs never studied in MPM at several doses, plus four already reported as active. Five of these new drugs, the most toxic, were studied further. In follow-up assays at 0.1 µM, alexidine caused no significant change in growth, caspase activation or colony formation. Cephalomannine, ouabain, thonzonium bromide and emetine reduced colony formation in all lines tested and growth in some or all lines. Caspase activation, a cell-death marker, rose in all lines with cephalomannine but only some with the other three. In a second panel including patient-derived tumour cells, viability fell in almost all MPM cultures, less so in non-malignant cells. The authors concluded these four drugs warrant further laboratory and animal testing. They noted the single-dose screen may have missed candidates and that normal pleural cells were scarce.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) drug-repurposing screen on cell lines, re-analysing an earlier screen of 1170 drugs, followed by dose-response, proliferation, caspase, colony-formation and spheroid assays
• Who was studied: Human cell lines. Malignant: Mero-14, Mero-25, IST-Mes2, NCI-H28, MSTO-211H, Mero-41, Mero-95, ZL55 and REN. Non-malignant: MeT-5A and LP-9, plus HMC7, a primary culture from a spontaneous pneumothorax. Primary cell lines from MPM patients: MMP1, MMP2 and MMP4.
• Exposure: No asbestos exposure was studied. The cells were treated with a library of 1170 FDA-approved drugs, first at a single dose of 10 µM and then, for selected drugs, at 0.1, 1, 10 and 100 µM.
• Main results:
  • The re-evaluation identified 90 drugs that were toxic to at least four of the five MPM cell lines, and to varying extents also to the MeT-5A line.
  • Of the 56 drugs never tested in MPM models, 38 were tested at several doses. Four drugs already published as active in MPM were included as controls.
  • Cephalomannine, ouabain, alexidine, thonzonium bromide and emetine were chosen for further study because they showed the strongest cytotoxicity.
  • Cephalomannine caused a statistically significant activation of caspases-3 and -7 in all cell lines, and it inhibited colony formation in all cell lines (p less than 0.0001).
  • In the follow-up assays, alexidine at 0.1 µM produced no significant changes in any cell line in proliferation, caspase activation or colony formation. It was dropped from further analysis.
  • Ouabain activated caspases in all lines except MeT-5A and MSTO-211H.
  • Thonzonium bromide inhibited colony formation in all cell lines (p less than 0.0001). It activated caspase-3 and -7 only in Mero-25 and MSTO-211H.
  • Emetine significantly reduced proliferation only in Mero-14, IST-Mes2 and MSTO-211H at 72 h (p less than 0.0001). It prevented all cell lines from forming colonies.
  • In a second panel of MPM cell lines, the four drugs significantly reduced viability in almost all lines. The exceptions were cephalomannine in Mero-41 and thonzonium bromide in Mero-95.
  • Among non-malignant cells, viability fell significantly only in HMC7 treated with cephalomannine and emetine, and in LP-9 treated with cephalomannine.
  • Patient-derived MPM cell cultures responded to all four drugs, except MMP2 treated with thonzonium bromide.
• The authors' conclusion: The authors concluded that cephalomannine, ouabain, thonzonium bromide and emetine showed marked activity on MPM cells. In their view, this warrants further laboratory and animal experiments, including work to find out how the drugs act.
• Limitations the authors state:
  • The initial single-dose screen may have missed some promising drugs.
  • Few primary non-malignant cells from normal pleura were available. Substitute controls could bias the results.
  • MeT-5A cells may not be the most appropriate model of non-malignant mesothelial cells.
  • Further studies are needed to define doses that would work with the least toxicity in living organisms.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, SV40.

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