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J. Biol. Chem., Vol. 276, Issue 41, 37747-37753, October 12, 2001
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From the Chronic myeloid leukemia cells
contain a constitutively active Bcr-Abl tyrosine kinase, the target
protein of Gleevec (STI571) phenylaminopyrimidine class protein kinase
inhibitor. Here we provide evidence for metabolic phenotypic
changes in cultured K562 human myeloid blast cells after treatment with
increasing doses of STI571 using
[1,2-13C2]glucose as the single tracer
and biological mass spectrometry. In response to 0.68 and 6.8 µM STI571, proliferation of Bcr-Abl-positive K562
cells showed a 57% and 74% decrease, respectively, whereas glucose
label incorporation into RNA decreased by 13.4% and 30.1%, respectively, through direct glucose oxidation, as indicated by the
decrease in the m1/
Gleevec (STI571) Influences Metabolic Enzyme Activities and
Glucose Carbon Flow toward Nucleic Acid and Fatty Acid Synthesis in
Myeloid Tumor Cells*
§,,,,,
Department of Biochemistry and Molecular
Biology, Institut d'Investigacions Biomediques August Pi i Sunyer,
University of Barcelona, Marti i Franques 1, Barcelona 08028, Spain and
¶ UCLA School of Medicine, Harbor-UCLA Research and Education
Institute, Torrance, California 90502
mn
ratio in RNA. Based on the in vitro proliferation data, the
IC50 of STI571 in K562 cultures is 0.56 µM.
The decrease in 13C label incorporation into RNA ribose was
accompanied by a significant fall in hexokinase and glucose-6-phosphate
1-dehydrogenase activities. The activity of transketolase, the enzyme
responsible for nonoxidative ribose synthesis in the pentose cycle, was
less affected, and there was a relative increase in glucose carbon
incorporation into RNA through nonoxidative synthesis as indicated by
the increase in the
m2/mn ratio in RNA. The
restricted use of glucose carbons for de novo nucleic acid
and fatty acid synthesis by altering metabolic enzyme activities and
pathway carbon flux of the pentose cycle constitutes the underlying
mechanism by which STI571 inhibits leukemia cell glucose substrate
utilization and growth. The administration of specific
hexokinase/glucose-6-phosphate 1-dehydrogenase inhibitor anti-metabolite substrates or competitive enzyme inhibitor compounds, alone or in combination, should be explored for the treatment of
STI571-resistant advanced leukemias as well as that of Bcr-Abl-negative human malignancies.
*
This work was supported in part by Grant PHS
M01-RR0045 of the General Clinical Research Unit, Grant
P01-CA42710 of the UCLA Clinical Nutrition Research Unit Stable Isotope
Core through its preliminary/feasibility grant program, grants from the
Spanish government Science and Technology Ministry
(PPQ2000-0688-C05-04) and Health Ministry (FISS00/1120), and a grant
from the NATO Science Program (SA.LST.CLG.976283).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Stable Isotope
Research Laboratory, UCLA School of Medicine, Harbor-UCLA Research and
Education Institute, 1124 W. Carson St. RB1, Torrance, CA 90502. Tel.:
310-222-1886; Fax: 310-222-3887; E-mail: boros@gcrc.humc.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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