Abstract
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.
Highlights
Glioblastoma (GBM) is the most common, heterogeneous and aggressive primary brain tumor in adults (54% of all gliomas) [1,2,3]
To better understand if the vast molecular landscape of GBM could be reduced into a manageable number of metabolic categories, we explored the The Cancer Genome Atlas (TCGA) expression databases using a Gene Set Variation Analysis (GSVA) approach
Idative pathways, Warburg-like phenotypes were enriched in the mesenchymal subgroup, whereas functional mitochondrial metabolism predominated in healthy tissues (Figure 1a)
Summary
Glioblastoma (GBM) is the most common, heterogeneous and aggressive primary brain tumor in adults (54% of all gliomas) [1,2,3]. The World Health Organization (WHO, Geneva, Switzerland) classifies GBM based on histopathological findings and molecular features (especially IDH mutation status) [4]. At a gene-expression level, GBM can be classified into four subtypes: mesenchymal, classical, proneural and neural [5,6]. GBM has a low global incidence (less than 10 per 100,000 persons/year), but cumulative survival after five years from diagnosis is less than 10%, making it a critical public health issue [8,9]. As standard of care is not a curative option, new therapies are sorely needed, with efforts to characterize GBM from multiple viewpoints, predominantly the omics sciences
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