Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma
In: http://lobid.org/resources/99370671962606441#!, 122(8):1146-1157, 2020
academicJournal
Zugriff:
Background!#!Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma.!##!Methods!#!Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM).!##!Results!#!ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM.!##!Conclusion!#!Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.
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Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma
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Autor/in / Beteiligte Person: | Pruss, Maximilian ; Dwucet, Annika ; Tanriover, Mine ; Hlavac, Michal ; Kast, Richard Eric ; Debatin, Klaus-Michael ; Wirtz, Christian Rainer ; Halatsch, Marc-Eric ; Siegelin, Markus David ; Westhoff, Mike-Andrew ; Karpel-Massler, Georg |
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Zeitschrift: | http://lobid.org/resources/99370671962606441#!, 122(8):1146-1157, 2020 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41416-020-0759-0 |
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