ArticleCancer & metabolism2021
Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma.
Article in Cancer & metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 22 citations in OpenAlex.
- Context-dependent synthetic lethality - an emerging precision therapeutic approach.Nature reviews. Cancer · 2026Review
- 1p/19q codeletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas.Neuro-oncology · 2026Article
- Metabolic Imprint of Poliovirus on Glioblastoma Cells and Its Role in Virus Replication and Cytopathic Activity.International journal of molecular sciences · 2025Article
- Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues.Molecular biology reports · 2025Review
- Beyond glucose and Warburg: finding the sweet spot in cancer metabolism models.npj metabolic health and disease · 2024Review
- Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.Cells · 2024Article
- Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.ASN neuro · 2024Article
- Bridging the gap: advancing cancer cell culture to reveal key metabolic targets.Frontiers in oncology · 2024Review
- BeyondMolecular therapy oncolytics · 2023Review
- Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.International journal of molecular sciences · 2023Review
- Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism.bioRxiv : the preprint server for biology · 2023Article
- Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines.Cancers · 2023Article
- Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment ofJournal of medicinal chemistry · 2022Article
- Physiological Media in Studies of Cell Metabolism.Molecular biology · 2022Article
- Augmented Therapeutic Potential of Glutaminase Inhibitor CB839 in Glioblastoma Stem Cells Using Gold Nanoparticle Delivery.Pharmaceutics · 2021Article
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Authors and funding
16 authors at 4 institutions in 1 country.
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Abstract
backgroundReprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839.
methodsWe analyzed polar metabolites in sensitive (ENO1-deleted) and resistant (ENO1-WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models.
resultsMetabolomic profiling of ENO1-deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1-deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media Plasmax
conclusionTogether, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo-unlike cells in culture-show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.
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