title: Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells.
abstract: 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 microm 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/Sigma(m)n ratio in RNA. Based on the in vitro proliferation data, the IC50 of STI571 in K562 cultures is 0.56 microm. 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/Sigma(m)n 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Marti i Franques 1, Barcelona 08028, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Boren
authors.forename: M
authors.initials: M
authors.lastname: Cascante
authors.forename: S
authors.initials: S
authors.lastname: Marin
authors.forename: B
authors.initials: B
authors.lastname: Comín-Anduix
authors.forename: J J
authors.initials: JJ
authors.lastname: Centelles
authors.forename: S
authors.initials: S
authors.lastname: Lim
authors.forename: S
authors.initials: S
authors.lastname: Bassilian
authors.forename: S
authors.initials: S
authors.lastname: Ahmed
authors.forename: W N
authors.initials: WN
authors.lastname: Lee
authors.forename: L G
authors.initials: LG
authors.lastname: Boros
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002244:Carbon / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis*; D005947:Glucose / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009696:Nucleic Acids / Q000096:biosynthesis*; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D014174:Transketolase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D009696:Nucleic Acids; D010879:Piperazines; D011743:Pyrimidines; D002244:Carbon; D000068877:Imatinib Mesylate; D005954:Glucosephosphate Dehydrogenase; D014174:Transketolase; D006593:Hexokinase; D011505:Protein-Tyrosine Kinases; D005947:Glucose