2-Deoxyglucose improves sensitivity of leukemia drug-resistant K562/ADM cells to adriamycin by blocking aerobic glycolysis
ZHANG Xue-yan;AI Zi-ying;GOU Ze-peng;CHEN Jing;YI Juan;ZHAO Huai-shun;WEI Hu-lai;School of Basic Medical Science,Lanzhou University,Key Laboratory of Preclinical Study for New Drugs of Gansu Province;Outpatient Department,Institution Hospital of Lanzhou Military Region;
Aim To investigate the effect of 2-deoxyD-glucose( 2-DG) on the sensitivity of leukemia multidrug resistant K562 / ADM cells to adriamycin by inhibiting glycolytic pathway as well as its molecular mechanisms. 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 glycolysis including glucose consumption,lactate export,and hexokinase activity was determined by glucose,lactic acid and hexokinase( HK) testing kits. The expression and phosphorylation of mammalian target of rapamycin( m TOR) 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 m TOR. However,the co-administration of 2-DG and adriamycin markedly counteracted adriamycin-mediated enhancement of m TOR expression and phosphorylation and down-regulated 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 enhances the sensitivity to adriamycin by blocking aerobic glycolysis pathway through inhibiting hexokinase activity,counteracting adriamycin-stimulated increased expression and phosphorylation of m TOR and downregulating GLUT-4 expression.
【Fund】： 国家自然科学基金资助项目(No 81541025 81141053);; 兰州大学中央高校基本科研业务费专项资金资助项目(No lzujbky-2014-136)
【CateGory Index】： R96
【CateGory Index】： R96