2-Deoxyglucose improves sensitivity of leukemia drug-resistant K562/ADM cells to adriamycin by blocking aerobic glycolysis / 中国药理学通报

ABSTRACT

Aim To investigate the effect of 2-deoxy-D-glucose(2-DG)on the sensitivity of leukemia multi-drug resistant K562/ADMcells to adriamycin by inhib-iting glycolytic pathway as well as its molecular mecha-nisms.Methods The leukemia drug-resistant K562/ADM cells and parental K562 cells were used as the target cell models.The cell proliferating activity was assessed with an MTT colorimetric assay,and the gly-colysis including glucose consumption,lactate export, and hexokinase activity was determined by glucose, lactic acid and hexokinase (HK)testing kits.The ex-pression and phosphorylation of mammalian target of rapamycin(mTOR)and glucose transporter-4 (GLUT-4)expression were analyzed by western blot.Results K562/ADM drug-resistant cells possessed higher HK activity,GLUT-4 expression level and aerobic glycolic ability than K562 sensitive cells. 2-DG treatment markedly inhibited HK activity,glucose consumption, and lactate export both in K562 cells and K562/ADM cells,and suppressed the proliferation of the two cells in a time-and concentration-dependent manner.Low concentration of 2-DG or adriamycin could increase the expression and phosphorylation of mTOR.However, the co-administration of 2-DG and adriamycin markedly counteracted adriamycin-mediated enhancement of mTOR expression and phosphorylation and down-regu-lated GLUT-4 expression in K562/ADM cells,and 2-DG dramatically improved the sensitivity of K562/ADM cells to cytotoxicity.Conclusion 2-DG inhibits the proliferation of drug-resistant K562/ADM cells and en-hances the sensitivity to adriamycin by blocking aerobic glycolysis pathway through inhibiting hexokinase activi-ty,counteracting adriamycin-stimulated increased ex-pression and phosphorylation of mTOR and downregu-lating GLUT-4 expression.