This title appears in the Scientific Report :
2020
Please use the identifier:
http://hdl.handle.net/2128/25101 in citations.
Please use the identifier: http://dx.doi.org/10.1038/s41420-020-0258-3 in citations.
A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity
A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity
Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply ofmacromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy.Several tumors excessively metabolize glutamine to generate precursors for n...
Saved in:
Personal Name(s): | Koch, Katharina |
---|---|
Hartmann, Rudolf / Tsiampali, Julia / Uhlmann, Constanze / Nickel, Ann-Christin / He, Xiaoling / Kamp, Marcel A. / Sabel, Michael / Barker, Roger A. / Steiger, Hans-Jakob / Hänggi, Daniel / Willbold, Dieter / Maciaczyk, Jaroslaw / Kahlert, Ulf D. (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; IBI-7 |
Published in: | Cell death discovery, 6 (2020) 1, S. 20 |
Imprint: |
London
Nature Publishing Group816700
2020
|
PubMed ID: |
32337072 |
DOI: |
10.1038/s41420-020-0258-3 |
Document Type: |
Journal Article |
Research Program: |
Engineering Cell Function |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1038/s41420-020-0258-3 in citations.
Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply ofmacromolecular 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 therapyresistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectivelydiminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolicstudies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivatesinto the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivitymarkedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models ascompared 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. |