Metabolic characteristics of imatinib resistance in chronic myeloid leukaemia cells

Klawitter, Jelena; Kominsky, Douglas J.; Brown, Jaimi L.; Klawitter, Jost; Christians, Uwe; Leibfritz, Dieter; Melo, Junia V.; Eckhardt, S. Gail; Serkova, Natalie J.

doi:10.1111/j.1476-5381.2009.00345.x

Cited by 56 publications

(55 citation statements)

References 35 publications

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“…However, the evaluation of the mean quantity of drug in each cell showed that the intracellular concentration was markedly higher than the extracellular concentration, indicating a predominantly active mechanism (13,25). Although this process is not fully understood, it probably involves a saturable-type transporter (26).…”

Section: Discussionmentioning

confidence: 99%

Measurement of imatinib uptake by flow cytometry

Bourgne¹,

Bamdad²,

Janel³

et al. 2012

Cytometry Pt A

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One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry. In two CML cell lines, we obtained a satisfactory relationship between intracellular IM (ICIM) levels and media concentrations, and we found a strong correlation between ICIM at 1 h and IM efficacy at 24 h, demonstrating that ICIM at 1 h might be a relevant predictive parameter of cell sensitivity. Our method was more sensitive than the standard physicochemical method. We applied our method to primary cells and found cell morphology-dependant IM accumulation. Moreover, in CML cells from patients at diagnosis, IM accumulation was heterogeneous. In all cases, ICIM at the single-cell level was much higher than in culture media arguing in favor of a predominantly active uptake process. We developed a simple method directly applicable to primary cells that has shown two major advantages: only a small number of cells are required, and cell subsets can be identified according to morphological criteria and/or the presence of particular antigenic sites. This method provides a new tool to assess CML cell sensitivity to IM, and ICIM levels in native CML cells could be used to monitor therapeutic response. ' 2012 International Society for Advancement of Cytometry

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Section: Discussionmentioning

confidence: 99%

Measurement of imatinib uptake by flow cytometry

Bourgne¹,

Bamdad²,

Janel³

et al. 2012

Cytometry Pt A

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“…For example, imatinib treatment of chronic myeloid leukemia cells induces a shift from glycolysis to mitochondrial metabolism, a phenotype associated with non-cancerous tissues (90,91). Imatinib-resistant cells display no such decrease in glycolysis in response to drug treatment.…”

Section: Applications Of Sirm In Drug Developmentmentioning

confidence: 99%

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.Metabolism is the collection of predominantly enzyme-catalyzed biochemical transformations that meet the growth and survival demands of an organism. For nearly a century, scientists have documented profound metabolic changes that occur in tumors (1, 2). One of the earliest insights into cancer metabolism came when Otto Warburg noted increased uptake and fermentation of glucose (Glc) 3 to lactate in tumors relative to surrounding tissue, even in the presence of ample oxygen (2). Clinical cancer diagnosis exploits this "Warburg effect" by measuring uptake of the Glc analogue 18 F-deoxyglucose using positron emission tomography (PET), as the metabolic demands of differentiated, non-proliferating tissues generally require far less Glc than tumors (3).Oncoproteins and tumor suppressors are well-established regulators of metabolism, and mutations or dysregulated expression can lead to the altered metabolic phenotypes observed in many cancers (4, 5). Inactivating mutations in enzymes such as fumarate hydratase (FH) or succinate dehydrogenase (SDH) induce pathophysiological accumulation of substrates that inhibit other critical enzyme functions, whereas less common gain-of-function mutations such as in isocitrate dehydrogenases (IDH) produce metabolites that directly deregulate cellular processes (6). Additionally, cancer cells frequently express fetal isoforms of metabolic enzymes that are subject to different regulatory mechanisms to provide growth advantages (7). Gaining a systematic understanding of the metabolic changes that occur during carcinogenesis can thus be exploited for therapeutic and diagnostic purposes.Stable isotope-resolved metabolomics (SIRM) is a powerful approach developed by others and by us where isotopically enriched precursors such as [ 13 C 6 ]Glc are administered to a biological system, and the ensuing metabolic transformations are determined using appropriate analytic techniques to enable robust reconstruction of metabolic pathways (8 -11). Stable isotopes are non-radioactive and in SIRM practice are identical chemically and functionally to the most abundant isotope of that element. Incorporating stable isotopes such as 2 H, 13 C, or 15 N into biological precursors has long been used to trace their metabolism in living systems (12). SIRM is thus distinct from non-tracer-based metabolomics profiling for statistical models. Here, we review SIRM applications and demonstrate h...

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“…Previous studies have investigated altered glucose metabolism in chemoresistant leukemia cells (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). It has been reported that prednisolone resistance in patients with precursor B-cell acute lymphoblastic leukemia (ALL) was associated with an increased expression of genes involved in glucose metabolism (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that prednisolone resistance in patients with precursor B-cell acute lymphoblastic leukemia (ALL) was associated with an increased expression of genes involved in glucose metabolism (5,6). Imatinib-resistant chronic myelogenous leukemia cells also exhibited a high glycolysis phenotype, with elevated glucose uptake and lactate production compared with imatinib-sensitive cells (7)(8)(9)(10). In addition, AML cell lines with an increased level of glycolysis showed increased resistance to the induction of apoptosis in vitro due to a combination of all-trans retinoic acid and arsenic trioxide (11).…”

Section: Introductionmentioning

confidence: 99%

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Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia

Song

et al. 2016

Oncology Letters

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Abstract. Altered glucose metabolism has been described as a cause of chemoresistance in multiple tumor types. The present study aimed to identify the expression profile of glucose metabolism in drug-resistant acute myeloid leukemia (AML) cells and provide potential strategies for the treatment of drug-resistant AML. Bone marrow and serum samples were obtained from patients with AML that were newly diagnosed or had relapsed. The messenger RNA expression of hypoxia inducible factor (HIF)-1α, glucose transporter (GLUT)1, and hexokinase-II was measured by quantitative polymerase chain reaction. The levels of LDH and β subunit of human F1-F0 adenosine triphosphate synthase (β-F1-ATPase) were detected by enzyme-linked immunosorbent and western blot assays. The HL-60 and HL-60/ADR cell lines were used to evaluate glycolytic activity and effect of glycolysis inhibition on cellular proliferation and apoptosis. Drug-resistant HL-60/ADR cells exhibited a significantly increased level of glycolysis compared with the drug-sensitive HL-60 cell line. The expression of HIF-1α, hexokinase-II, GLUT1 and LDH were increased in AML patients with no remission (NR), compared to healthy control individuals and patients with complete remission (CR) and partial remission. The expression of β-F1-ATPase in patients with NR was decreased compared with the expression in the CR group. Treatment of HL-60/ADR cells with 2-deoxy-D-glucose or 3-bromopyruvate increased in vitro sensitivity to Adriamycin (ADR), while treatment of HL-60 cells did not affect drug cytotoxicity. Subsequent to treatment for 24 h, apoptosis in these two cell lines showed no significant difference. However, glycolytic inhibitors in combination with ADR increased cellular necrosis. These findings indicate that increased glycolysis and low efficiency of oxidative phosphorylation may contribute to drug resistance. Targeting glycolysis is a viable strategy for modulating chemoresistance in AML.

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Metabolic characteristics of imatinib resistance in chronic myeloid leukaemia cells

Cited by 56 publications

References 35 publications

Measurement of imatinib uptake by flow cytometry

Measurement of imatinib uptake by flow cytometry

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia

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