Gleevec (ST1571) influences metabolic enzyme activities and glucose carbonflow toward nucleic acid and fatty acid synthesis in myeloid tumor cells

Citation
J. Boren et al., Gleevec (ST1571) influences metabolic enzyme activities and glucose carbonflow toward nucleic acid and fatty acid synthesis in myeloid tumor cells, J BIOL CHEM, 276(41), 2001, pp. 37747-37753
Citations number
30
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
41
Year of publication
2001
Pages
37747 - 37753
Database
ISI
SICI code
0021-9258(20011012)276:41<37747:G(IMEA>2.0.ZU;2-H
Abstract
Chronic myeloid leukemia cells contain a constitutively active Bcr-Abl tyro sine kinase, the target protein of Gleevec (STI571) phenylaminopyrimidine c lass protein kinase inhibitor. Here we provide evidence for metabolic pheno typic changes in cultured K562 human myeloid blast cells after treatment wi th increasing doses of STI571 using [1,2-C-13(2)]glucose as the single trac er and biological mass spectrometry. In response to 0.68 and 6.8 mum STI571 , proliferation of Bcr-Abl-positive K562 cells showed a 57% and 74% decreas e, respectively, whereas glucose label incorporation into RNA decreased by 13.4% and 30.1%, respectively, through direct glucose oxidation, as indicat ed by the decrease in the m(1)/Sigmam(n) ratio in RNA. Based on the in vitr o proliferation data, the IC50 of STI571 in K562 cultures is 0.56 mum. The decrease in C-13 label incorporation into RNA ribose was accompanied by a s ignificant fall in hexokinase and glucose-6-phosphate 1-dehydrogenase activ ities. The activity of transketolase, the enzyme responsible for nonoxidati ve ribose synthesis in the pentose cycle, was less affected, and there was a relative increase in glucose carbon incorporation into RNA through nonoxi dative synthesis as indicated by the increase in the m(2)/Sigmam(n) ratio i n RNA. The restricted use of glucose carbons for de novo nucleic acid and f atty acid synthesis by altering metabolic enzyme activities and pathway car bon flux of the pentose cycle constitutes the underlying mechanism by which STI571 inhibits leukemia cell glucose substrate utilization and growth. Th e administration of specific hexokinase/glucose-6-phosphate 1-dehydrogenase inhibitor anti-metabolite substrates or competitive enzyme inhibitor compo unds, alone or in combination, should be explored for the treatment of STI5 71-resistant advanced leukemias as well as that of Ber-Abl-negative human m alignancies.