Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux through downregulation of GLUT-1 transporters in human leukemia cells. This mechanism has the potential to induce regression of type 2 diabetes and hyperlipidemia as observed in patients with chronic myeloid leukemia or hypereosinophilic syndrome. In addition, there is a stimulatory effect of IM on differentiation of human mesenchymal stem cells. Its synergism with retinoic acid or low dose Ara-C is applied in treatment of acute myeloid leukemia (AML). Thus, the AML-derived c-kit positive cell line HL60 was chosen for studying the effect of IM on expression of genes associated with differentiation and metabolism. We analysed the possible feedback on transcription factors (AML1 and AML3) and consequences regarding differentiation and metabolism - associated genes. Quantitative reverse transcriptase PCR analyses revealed that IM treatment of HL60 cells downregulates mRNA synthesis of AML1 and AML3 by 70% without affecting transcription of the c-abl tyrosine kinase. IM reduces expression of CD34 mRNA from 20% to 6% of the housekeeping gene G6PD. The appearance of differentiated cells was accompanied by a remarkable stimulation of mRNAs from CD11b and CD14 (monocyte markers) reaching 4-fold higher expression levels relative to G6PD. This was associated with an increased proportion of osteocalcin (OCN), which has recently been shown to enhance mitochondrial activity. A 2-fold stimulation of a fat-metabolism associated mitochondrial palmitoyltransferase (CPT1B) and 10-fold stimulation of microsomal carnitine palmitoyltransferase and the carnitine transporter OCTN2 supports previous data indicating an IM-associated stimulation of oxidative metabolism resulting in a regression of type-2 diabetes and hyperlipidemia. Our current investigations show that IM-associated attenuation of cell proliferation inhibited transcription factors AML1 and AML3 and triggered differentiation in the leukemic cell line HL60, as reflected by altered mRNA expression of surface marker genes. The IM - induced stimulation of lipid metabolism in HL60 confirms previous data indicating a reversal of the Warburg effect in K562 cells without cytocidal activity. This indicates a similar mechanism as known for other drugs and strategies targeting glucose or fat metabolism, which are discussed in the context of cancer prevention and treatment.
Disclosure: No relevant conflicts of interest to declare.