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 [1,2-13 C 2 ]glucose as the single tracer and biological mass spectrometry. In response to 0.68 and 6.8 M 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 m 1 /⌺m n ratio in RNA. Based on the in vitro proliferation data, the IC 50 of STI571 in K562 cultures is 0.56 M. The decrease in 13 C 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 m 2 /⌺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.

Metabolic alterations mediated by STAT3 promotes drug persistence in CML

“…LSCs have an increased oxygen consumption rate upon initial drug treatment [53]; however, our data suggest that with prolonged treatment, the more quiescent, TKI-persistent cells are biased towards glycolysis, possibly due to reduced energy requirements. Additionally, reductive carboxylation, a de novo lipogenesis pathway [69], and elongation of fatty acids in TKI-persistent K562 are consistent with utilization of carbon from glucose for nucleic acid and fatty acid synthesis [54,70]. Moreover, free fatty acids can form a feedforward loop with fatty acid oxidation, a reserve energy source [71].…”

“…CML stem and progenitor cells rely on oxidative phosphorylation compared to their non-transformed counterparts [44,53]. Moreover, short-term TKI-treatment of sensitive cells reduces glucose uptake and its utilization for nucleotide and fatty acid synthesis while increasing mitochondrial activity [54,55], but alterations in the metabolism of IM-persistent CML cells is yet to be studied. Thus, to examine metabolic differences between sensitive and IM-persistent K562, we measured cellular mitochondrial function and glycolysis using extracellular flux analyzer.…”

Identification of Novel Small-Molecule Inhibitors for Human Transketolase by High-Throughput Screening with Fluorescent Intensity (FLINT) Assay

“…Recent studies analyzing glucose metabolic pathways using biological mass spectrometry have shown that several chemicals and natural products inhibit cell proliferation or tumor growth through regulation of glucose intermediate metabolism targeted at the oxidative PPP, the nonoxidative PPP, or both. 6,[11][12][13][14]20,21 The tyrosine kinase inhibitor genistein inhibits tumor growth primarily through the regulation of glucose metabolism, specifically targeting the nonoxidative PPP. 11 Avemar inhibits metastasis formation also primarily through the nonoxidative PPP, and it decreases activities of glucose-6-phosphate 1-dehydrogenase (G6PDH), a key enzyme in the oxidative PPP, as well as TK.…”

“…G6PDH and another key enzyme controlling oxidative reactions, hexokinase, are both inhibited by Gleevec treatment. 20 Methotrexate (MTX), currently in trials for colorectal carcinoma, inhibits the activity of G6PDH and 6-phosphogluconate dehydrogenases, both involved in oxidative PPP. 22 All these data suggest that inhibition of the glucose metabolism pathway may contribute significantly to the effects of cell proliferation and/or tumor growth inhibition and that inhibition of the glucose metabolism pathway may potentially be an effective way to treat cancer, a so-called "cancer starvation" strategy.…”

Imatinib Mesylate as an Effective Anti-viral Treatment for Alphavirus Infections

“…Imatinib mesylate, or Gleevec®, is a tyrosine kinase inhibitor that prevents the phosphorylation and activation of key enzymes in metabolic pathways (1). Specifically, Imatinib has been shown to reduce the activity of hexokinase, which is a key enzyme in the glycolysis pathway (3,18). Sindbis virus is dependent on glycolysis and it was predicted that inhibiting the glycolytic pathway would result in less viral replication.…”