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A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Koch, Katharina 
Hartmann, Rudolf 
Tsiampali, Julia 
Uhlmann, Constanze 
Nickel, Ann-Christin 

Abstract

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.

Description

Keywords

CNS cancer, Cancer metabolism, Cancer stem cells, Predictive markers, Translational research

Journal Title

Cell Death Discov

Conference Name

Journal ISSN

2058-7716
2058-7716

Volume Title

6

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_PC_12009)
Medical Research Council (MC_PC_17230)