A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity.
CNS cancer
Cancer metabolism
Cancer stem cells
Predictive markers
Translational research
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
2020
2020
Historique:
received:
12
12
2019
revised:
27
02
2020
accepted:
26
03
2020
entrez:
28
4
2020
pubmed:
28
4
2020
medline:
28
4
2020
Statut:
epublish
Résumé
Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment.
Identifiants
pubmed: 32337072
doi: 10.1038/s41420-020-0258-3
pii: 258
pmc: PMC7162917
doi:
Types de publication
Journal Article
Langues
eng
Pagination
20Subventions
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020.
Déclaration de conflit d'intérêts
Conflict of interestThe authors declare that they have no conflict of interest.
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