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Open AccessArticle

Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma

1
Faculty of Medicine, Institute for Applied Molecular Medicine (IMMA), CEU San Pablo University, 28668 Madrid, Spain
2
Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Madrid, Spain
3
Brain Tumor Laboratory, Fundación Vithas, Grupo Hospitales Vithas, 28043 Madrid, Spain
4
Fundación de Investigación HM Hospitales, HM Hospitales, 28015 Madrid, Spain
5
Neurosurgery Department, Hospital Universitario La Fe, 46026 Valencia, Spain
6
Departamento de Medicina Nuclear, HM Hospitales, 28015 Madrid, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Javier S. Castresana
Cells 2021, 10(2), 202; https://doi.org/10.3390/cells10020202
Received: 31 December 2020 / Revised: 16 January 2021 / Accepted: 18 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs. View Full-Text
Keywords: glioblastoma; energy metabolism; glycolysis; oxidative phosphorylation; therapeutics; gene expression profiling glioblastoma; energy metabolism; glycolysis; oxidative phosphorylation; therapeutics; gene expression profiling
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MDPI and ACS Style

Duraj, T.; García-Romero, N.; Carrión-Navarro, J.; Madurga, R.; Ortiz de Mendivil, A.; Prat-Acin, R.; Garcia-Cañamaque, L.; Ayuso-Sacido, A. Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma. Cells 2021, 10, 202. https://doi.org/10.3390/cells10020202

AMA Style

Duraj T, García-Romero N, Carrión-Navarro J, Madurga R, Ortiz de Mendivil A, Prat-Acin R, Garcia-Cañamaque L, Ayuso-Sacido A. Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma. Cells. 2021; 10(2):202. https://doi.org/10.3390/cells10020202

Chicago/Turabian Style

Duraj, Tomás; García-Romero, Noemí; Carrión-Navarro, Josefa; Madurga, Rodrigo; Ortiz de Mendivil, Ana; Prat-Acin, Ricardo; Garcia-Cañamaque, Lina; Ayuso-Sacido, Angel. 2021. "Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma" Cells 10, no. 2: 202. https://doi.org/10.3390/cells10020202

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