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70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12.05. - 15.05.2019, Würzburg

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Metabolic reprogramming following a combined treatment with imipridones and 2-deoxyglucose elicits energy depletion and synergistic anti-glioblastoma activity

Die gemeinsame Behandlung mit Imipridonen und 2-Deoxyglucose führt zur Energiedepletion und synergistischen anti-neoplastischen Aktivität im Glioblastom

Meeting Abstract

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  • Maximilian Pruss - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Annika Dwucet - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Mike-Andrew Westhoff - Universitätsklinikum Ulm, Klinik für Pädiatrie, Ulm, Deutschland
  • Michal Hlavac - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Markus David Siegelin - Columbia University Medical Center, Department of Pathology and Cell Biology, New York, NY, United States
  • Christian Rainer Wirtz - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • Marc-Eric Halatsch - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland
  • presenting/speaker Georg Karpel-Massler - Universitätsklinikum Ulm, Neurochirurgische Klinik, Ulm, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie. Würzburg, 12.-15.05.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocP054

doi: 10.3205/19dgnc392, urn:nbn:de:0183-19dgnc3926

Veröffentlicht: 8. Mai 2019

© 2019 Pruss 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

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Objective: The purpose of this study was to examine whether dual reprogramming of the metabolome of glioblastoma cells by imipridone-mediated OXPHOS inhibition and 2-deoxyglucose-mediated inhibition of glycolysis leads to enhanced anti-cancer activity.

Methods: Preclinical drug testing including extracellular flux analyses (agilent seahorse), MTT/CellTiter Glo-assays, flow cytometric analyses, transwell assays, time lapse live-cell microscopy and Western blot analyses were performed in different glioblastoma model systems including established and primary cultured glioblastoma cells.

Results: Our data show that treatment with the imipridone TIC10/ONC201 leads to a significant decrease in oxidative consumption rates (OCR) as measured by extracellular flux analysis. However, despite a remarkable suppression of OXPHOS, TIC10/ONC201-mediated effects on cell viability and migration are minor especially at lower concentrations. An increase of extracellular acidification rates (ECAR) following treatment with imipridones suggests a compensatory upregulation of glycolysis. In line with this finding, inhibition of glycolysis using 2-deoxyglucose leads to synergistic inhibitory effects on cellular viability and migration of established and primary cultured glioblastoma cells. On the molecular level, these biological effects are accompanied by a reduced expression of mitochondrial respiratory chain enzymes and a reduced phosphorylation of ERK and AKT.

Conclusion: Our data suggest that metabolic targeting of glioma cells by imipridones can be significantly enhanced by additional treatment with glycolysis inhibitors such as 2-deoxyglucose which translates into enhanced anti-cancer activity. Therefore, this metabolic multi-targeting strategy warrants further in vivo testing.