Document Detail


Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL-positive cells.
MedLine Citation:
PMID:  19401345     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The development of imatinib resistance has become a significant therapeutic problem in which the etiology seems to be multifactorial and poorly understood. As of today, clinical criteria to predict the development of imatinib resistance in chronic myelogenous leukemia (CML), other than rebound of the myeloproliferation, are under development. However, there is evidence that the control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib because imatinib-resistant gastrointestinal stromal KIT-positive tumors reveal highly elevated glucose uptake in radiologic images. We used nuclear magnetic resonance spectroscopy and gas chromatography mass spectrometry to assess (13)C glucose uptake and metabolism (glycolysis, TCA cycle, and nucleic acid ribose synthesis) during imatinib treatment in CML cell lines with different sensitivities to imatinib. Our results show that sensitive K562-s and LAMA84-s BCR-ABL-positive cells have decreased glucose uptake, decreased lactate production, and an improved oxidative TCA cycle following imatinib treatment. The resistant K562-r and LAMA84-r cells maintained a highly glycolytic metabolic phenotype with elevated glucose uptake and lactate production. In addition, oxidative synthesis of RNA ribose from (13)C-glucose via glucose-6-phosphate dehydrogenase was decreased, and RNA synthesis via the nonoxidative transketolase pathway was increased in imatinib-resistant cells. CML cells which exhibited a (oxidative/nonoxidative) flux ratio for nucleic acid ribose synthesis of >1 were sensitive to imatinib. The resistant K562-r and LAMA84-r exhibited a (oxidative/nonoxidative) flux ratio of <0.7. The changes in glucose uptake and metabolism were accompanied by intracellular translocation of GLUT-1 from the plasma membrane into the intracellular fraction in sensitive cells treated with imatinib, whereas GLUT-1 remained located at the plasma membrane in LAMA84-r and K562-r cells. The total protein load of GLUT-1 was unchanged among treated sensitive and resistant cell lines. In summary, elevated glucose uptake and nonoxidative glycolytic metabolic phenotype can be used as sensitive markers for early detection of imatinib resistance in BCR-ABL-positive cells.
Authors:
Douglas J Kominsky; Jelena Klawitter; Jaimi L Brown; Laszlo G Boros; Junia V Melo; S Gail Eckhardt; Natalie J Serkova
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-04-28
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  15     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-19     Completed Date:  2009-08-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3442-50     Citation Subset:  IM    
Affiliation:
Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, CO, USA. Douglas.Kominsky@ucdenver.edu
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Blotting, Western
Carbon Isotopes
Cell Line, Tumor
Deoxyglucose / metabolism,  pharmacokinetics
Drug Resistance, Neoplasm*
Gas Chromatography-Mass Spectrometry
Glucose / metabolism*,  pharmacokinetics
Glucose Transporter Type 1 / genetics,  metabolism*
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics,  metabolism,  pathology
Magnetic Resonance Spectroscopy / methods
Piperazines / pharmacology*
Protein Transport / drug effects
Pyrimidines / pharmacology*
RNA, Neoplasm / biosynthesis
Reverse Transcriptase Polymerase Chain Reaction
Ribose / biosynthesis
Time Factors
Grant Support
ID/Acronym/Agency:
P30 CA046934/CA/NCI NIH HHS; R21 CA108624/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carbon Isotopes; 0/Glucose Transporter Type 1; 0/Piperazines; 0/Pyrimidines; 0/RNA, Neoplasm; 152459-95-5/imatinib; 154-17-6/Deoxyglucose; 50-69-1/Ribose; 50-99-7/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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