Artikel
Drug repurposing of meclofenamate as a potent gap junction inhibitor sensities primary glioblastoma cells for lomustine
Meclofenamate als potenter pharmakologischer Gap junction Inhibitor sensitiviert Glioblastomzellen für einen durch Lomustin vermittelten Zelltod
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Autoren
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Matthias Schneider
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neurochirurgie, Bonn, Deutschland
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Anna-Laura Potthoff
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neurochirurgie, Bonn, Deutschland
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Kevin Joseph
- Albert-Ludwigs-Universität Freiburg, Forschungsgruppe Translationale Neuroonkologie, Freiburg, Deutschland; Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Freiburg, Deutschland; Albert-Ludwigs-Universität Freiburg, Abteilung für Neurochirurgie, Freiburg, Deutschland
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Bernd O. Evert
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neurologie, Bonn, Deutschland
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Erdem Güresir
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neurochirurgie, Bonn, Deutschland
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Patrick Schuss
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neurochirurgie, Bonn, Deutschland
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Andreas Dolf
- Rheinische Friedrich-Wilhelms-Universität Bonn, Institut für Experimentelle Immunologie, Bonn, Deutschland
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Mike-Andrew Westhoff
- Universitätsklinikum Ulm, Abteilung für Pädiatrie und Jugendmedizin, Ulm, Deutschland
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Andreas Waha
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neuropathologie, Bonn, Deutschland
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Oliver Schnell
- Albert-Ludwigs-Universität Freiburg, Forschungsgruppe Translationale Neuroonkologie, Freiburg, Deutschland; Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Freiburg, Deutschland; Albert-Ludwigs-Universität Freiburg, Abteilung für Neurochirurgie, Freiburg, Deutschland
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Hartmut Vatter
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Neurochirurgie, Bonn, Deutschland
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Dieter Henrik Heiland
- Albert-Ludwigs-Universität Freiburg, Forschungsgruppe Translationale Neuroonkologie, Freiburg, Deutschland; Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Freiburg, Deutschland; Albert-Ludwigs-Universität Freiburg, Abteilung für Neurochirurgie, Freiburg, Deutschland
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Ulrich Herrlinger
- Rheinische Friedrich-Wilhelms-Universität Bonn, Abteilung für Klinische Neuroonkologie, Bonn, Deutschland
| Veröffentlicht: | 26. Juni 2020 |
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Gliederung
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Objective: Since inhibition of a syncytial intercellular communication via gap junctions has been shown to sensitize glioblastoma cells to temozolomide-mediated antitumoral effects, the idea of gap junction-targeted therapies has been proposed as a promising novel therapeutic strategy within translational glioblastoma research. However, the impact of gap junction inhibition in the context of lomustine therapy that has recently been shown to markedly improve survival of glioblastoma patients in combination treatment with temozolomide, has not been examined, so far. By repurposing of meclofenamate (MFA) - a clinically approved nonsteroidal anti-inflammatory drug - as a potent gap junction inhibitor, the present study aimed at investigating the effects of a gap junction-targeted therapy on primary human glioblastoma cells in the context of lomustine administration.
Methods: In order to quantify the extent of gap junction inhibition, Realtime-Imaging fluorescence-guided measurements of calcein cell-to-cell cytoplasm transfer were performed. We used RNA-sequencing and proteome profiling to study the downstream signalling due to meclofenamate treatment. DNA-fragmentation served as readout for cell death and was assessed by flow cytometric analysis of propidium iodide-stained nuclei.
Results: We observed a significant reduction of calcein cytoplasm transfer in MFA-treated cells as well as reduction of cell-cell connection based on 3D-confocal reconstruction. RNA-sequencing revealed an increased stress-induced gene expression pattern in samples with pharmacological inhibition of gap junctions and CCNU therapy. The CX-43 inhibition profoundly increased the percentage of lomustine-mediated cell death. Gap junction inhibition was associated with elevated activity of the JNK signalling pathway.
Conclusion: This study is the first to show that inhibition of intercellular comunication via gap junctions profoundly sensitizes primary glioblastoma cells to lomustine-mediated cell death therefore constituting a promising new therapy strategy for patients suffering from this disastrous and currently incurable cancer. With regard to MFA as a clinically-approved drug, MFA might harbour the potential of bridging the idea of gap junction-targeted therapeutic approaches into an instant subsequent clinical implementation.
