Imatinib (STI571)-Mediated Changes in Glucose Metabolism in Human Leukemia BCR-ABL-Positive Cells

• Published in: Clinical cancer research Vol. 10; no. 19; pp. 6661 - 6668
• Main Authors: GOTTSCHALK, Sven, ANDERSON, Nora, HAINZ, Carsten, ECKHARDT, S. Gail, SERKOVA, Natalie J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2004
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzamides; Biological and medical sciences; Blotting, Western; Carbon Isotopes; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Fusion Proteins, bcr-abl - metabolism; Glucose - metabolism; Glucose - pharmacokinetics; Glutamates - metabolism; Humans; Imatinib Mesylate; K562 Cells; Lactates - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Magnetic Resonance Spectroscopy; Medical sciences; Nucleotides - metabolism; Pharmacology. Drug treatments; Phospholipids - metabolism; Piperazines - pharmacology; Pyrimidines - pharmacology; Tumors; Chromosomal aberration; Antineoplastic agent; Human; Imatinib; Enzyme; Transferases; Leukemia; Enzyme inhibitor; Malignant hemopathy; Glucose; Metabolism; Philadelphia chromosome; Abnormal chromosome C9; Protein kinase; Bcr-abl protein; Abnormal chromosome G22; Abnormal chromosome; Protein-tyrosine kinase; Hybrid gene; Chromosome translocation
• DOI: 10.1158/1078-0432.CCR-04-0039
• ISSN: 1078-0432

The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1- 13 C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC 50 , 0.69 ± 0.06 μmol/L) and K562 cells (IC 50 , 0.47 ± 0.04 μmol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1–1.0 μmol/L) decreased glucose uptake from the media by suppressing glycolitic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 μmol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 μmol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.