gms | German Medical Science

72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

06.06. - 09.06.2021

Drug repurposing of meclofenamate as a potent gap junction inhibitor sensitises primary glioblastoma cells for lomustine

Meclofenamat sensitiviert primäre Glioblastomzellen für einen durch Lomustin vermittelten Zelltod

Meeting Abstract

  • presenting/speaker Matthias Schneider - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland; Universitätsklinikum Bonn, Institut für Neuropathologie, Bonn, Deutschland
  • Anna-Laura Potthoff - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland
  • Bernd O. Evert - Universitätsklinikum Bonn, Klinik für Neurologie, Bonn, Deutschland
  • Erdem Güresir - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland
  • Andreas Dolf - Universitätsklinikum Bonn, Institute of Experimental Immunology, Bonn, Deutschland
  • Mike-Andrew Westhoff - University Medical Center Ulm, Department of Pediatrics and Adolescent Medicine, Ulm, Deutschland
  • Andreas Waha - Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland; Universitätsklinikum Bonn, Institut für Neuropathologie, Bonn, Deutschland
  • Hartmut Vatter - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland
  • Dieter Henrik Heiland - Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland
  • Patrick Schuss - Universitätsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland
  • Ulrich Herrlinger - Universitätsklinikum Bonn, Klinik für Neurologie, Abteilung für klinische Neuroonkologie, Bonn, Deutschland; Universitätsklinikum Bonn, Brain Tumor Translational Research Affiliation Bonn, Bonn, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie. sine loco [digital], 06.-09.06.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocV112

doi: 10.3205/21dgnc107, urn:nbn:de:0183-21dgnc1071

Veröffentlicht: 4. Juni 2021

© 2021 Schneider et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objective: Sine 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. Pharmacological inhibition of gap junctions 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.