Metabolic characteristics of imatinib resistance in chronic myeloid leukaemia cells.
OBJECTIVE
Early detection of resistance development is crucial for imatinib-based treatment in chronic myeloid leukaemia (CML) patients. We aimed to distinguish metabolic markers of cell resistance to imatinib.


METHODS
Two human imatinib-sensitive CML cell lines: LAMA84-s and K562-s, and their resistant counterparts: LAMA84-r and K562-r (both resistant to 1 microM imatinib), and K562-R (5 microM) were analysed by nuclear magnetic resonance spectroscopy to assess global metabolic profiling, including energy state, glucose and phospholipid metabolism.


RESULTS
We found, by Western blotting and flow cytometry, that the levels of Bcr-Abl tyrosine kinase and multi-drug resistance p-glycoprotein were inconsistent among resistant clones. On the other hand, phospholipid metabolism and lactate production were highly predictive for cell response to imatinib. As previously reported, sensitive cells showed significantly decreased glycolytic activity (lactate) and phospholipid synthesis (phosphocholine) as well as increased phospholipid catabolism (glycerophosphocholine) after 24 h of 1 microM imatinib treatment, which correlated with inhibition of cell proliferation and induction of apoptosis. In contrast to their sensitive counterparts, the K562-r, K562-R and LAMA84-r maintained increased phospholipid synthesis and glycolytic lactate production in the presence of 1 microM (K562-r and LAMA84-r) and 5 microM (K562-R) imatinib.


CONCLUSIONS
Specific metabolic markers for early detection of imatinib resistance, including increased glycolytic activity and phospholipid turnover, can be identified in resistant clones. Once validated in human isolated leukocytes, they may be used to monitor the responsiveness of CML patients to treatment.
Klawitter
Jelena
J
Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, CO 80045, USA.
Kominsky
Douglas J
DJ
Brown
Jaimi L
JL
Klawitter
Jost
J
Christians
Uwe
U
Leibfritz
Dieter
D
Melo
Junia V
JV
Eckhardt
S Gail
SG
Serkova
Natalie J
NJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D019344:Lactic Acid / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D010743:Phospholipids / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D010743:Phospholipids; D010879:Piperazines; D011743:Pyrimidines; D019344:Lactic Acid; D000068877:Imatinib Mesylate