Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma.
Animals
Antineoplastic Agents
/ pharmacology
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Chick Embryo
/ drug effects
Deoxyglucose
/ pharmacology
Energy Metabolism
/ drug effects
Glioblastoma
/ drug therapy
Glycolysis
/ drug effects
Humans
Imidazoles
/ pharmacology
Oxidative Phosphorylation
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
10
06
2019
accepted:
05
02
2020
revised:
08
01
2020
pubmed:
3
3
2020
medline:
31
12
2020
entrez:
3
3
2020
Statut:
ppublish
Résumé
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. 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). 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32115576
doi: 10.1038/s41416-020-0759-0
pii: 10.1038/s41416-020-0759-0
pmc: PMC7156767
doi:
Substances chimiques
Antineoplastic Agents
0
Imidazoles
0
Pyridines
0
Pyrimidines
0
Deoxyglucose
9G2MP84A8W
TIC10 compound
9U35A31JAI
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1146-1157Subventions
Organisme : NINDS NIH HHS
ID : K08 NS083732
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095848
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102366
Pays : United States
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