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Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia
Joana Pereira-Vieira1,2, Daniela D Weber3, Sâmia Silva4
1Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal.
Abstract:
Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.
Insights
Altered glucose metabolism contributes to chemoresistance in acute myeloid leukemia (AML). Targeting these metabolic changes, particularly in cytarabine (Ara-C)-resistant AML, offers a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Altered cellular metabolism, especially glycolysis, is linked to chemoresistance in acute myeloid leukemia (AML).
- Understanding the specific metabolic adaptations in AML cells that confer resistance to chemotherapy is crucial for developing effective treatments.
- The therapeutic potential of targeting metabolic pathways in drug-resistant AML remains an area requiring further investigation.
Purpose of the Study:
- To investigate the role of glucose metabolism in acquired resistance to cytarabine (Ara-C) in AML cells.
- To explore metabolic alterations as potential therapeutic targets in the context of Ara-C resistance in AML.
Main Methods:
- Induction of Ara-C resistance in AML cell lines through stepwise exposure to increasing drug concentrations.
- Characterization of Ara-C-resistant AML cells, including growth capacity, genetic alterations, metabolic profiling, and sensitivity to metabolic inhibitors.
- Comparative analysis of metabolic phenotypes between parental and resistant AML cell lines (KG-1 Ara-R and MOLM13 Ara-R).
Main Results:
- Ara-C-resistant AML cell lines (KG-1 Ara-R and MOLM13 Ara-R) exhibited distinct metabolic profiles compared to their parental counterparts.
- KG-1 Ara-R cells showed a heightened glycolytic phenotype, with differential sensitivity to the glycolytic inhibitor 3-bromopyruvate (3-BP) and increased sensitivity to phenformin.
- MOLM13 Ara-R cells maintained a glucose metabolism profile similar to parental cells and showed sensitivity to glycolytic inhibitors.
Conclusions:
- Acquired resistance to Ara-C in AML involves significant metabolic adaptations.
- These metabolic adaptations present viable therapeutic targets for overcoming chemoresistance in AML patients.
- Targeting specific metabolic pathways could offer new strategies for treating therapy-resistant AML.
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