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
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.