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维生素E琥珀酸酯下调mdr1/P-gp表达逆转K562/ADM耐药细胞的凋亡抑制

Vitamin E Succinate Overcomes Apoptosis Resistance in Multidrug-resistant K562/ADM Cells by Down-regulating Expression of mdr1 Gene and Its Product P-glycoprotein
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摘要 目的研究维生素E琥珀酸酯(VitaminEsuccinate,VES)诱导多药耐药K562/ADM细胞凋亡的分子机制。方法采用四氮唑蓝比色法(MTT)检测K562/ADM增殖活性;细胞形态学和AnnexinV/PI双标记法检测细胞凋亡;RT-PCR检测mdr1基因和Caspase-3基因mRNA的表达;流式细胞法(FCM)测定P-gp蛋白表达水平和Caspase-3活性。结果VES显著抑制K562/ADM细胞的增殖;经VES处理后细胞形态上出现典型的凋亡改变;AnnexinⅤ/PI双染检测凋亡细胞明显增加;mdr1mRNA表达和P-糖蛋白(P-glycoprotein,P-gp)合成明显降低,Caspase-3mRNA表达和Caspase-3活性显著增强;VES增加K562/ADM细胞对ADM的敏感性。结论VES诱导mdr1/P-gp高表达的K562/ADM耐药细胞凋亡,其主要机制为下调mdr1/P-gp表达而逆转P-gp介导的细胞凋亡抑制和耐药性。 Objective To explore the apoptotic effect of Vitamin E succinate(VES) on multidrug resistant leukemia K562/ADM cells and the possible molecular mechanisms. Methods Human muh:idrug-resistant leukemia cell line K562/ADM overexpressing mdrl gene was used as the target cells. The cell proliferating activity was assessed with a MTT colorimetric assay. The apoptosis of K562/ADM cells was investigated by optical and electronic microscopic morphology and Annexin V/PI staining. The expression of mdrl and Caspase-3 mRNAs was detected with RT PCR, and the P-glycoprotein (P-gp) expression and Caspase-3 activity were measured using flow cytometry. Results VES obviously inhibited the proliferation of K562/ADM cells. After VES-treatment, the typical apoptotic morphological changes were observed in K562/ADM cells, and the apoptosis rate of the cells by Annexin V/PI staining was greatly increased. The expression of mdrl mRNA and its product Pgp was markedly down-regulated, and the expression of Caspase-3 rnRNA and Caspase-3 activity up-regulated in VES-induced K562/ADM cells. VES significantly enhanced the sensitivity of K562/ADM cells to adriamycin. Conclusion VES induces apoptosis of drugresistant K562/ADM cells overexpressing mdrl/P gp, the possible mechanism is reversal of the P-gp-mediated apoptosis resistance and drug-resistance via down-regulation of mdrl/P-gp expression in drug-resistant K562/ADM cells.
出处 《肿瘤防治研究》 CAS CSCD 北大核心 2006年第9期638-641,F0003,共5页 Cancer Research on Prevention and Treatment
基金 甘肃省自然科学基金资助项目(ZR-97-068)
关键词 维生素 E琥珀酸酯 多药耐药 凋亡抑制 P-糖蛋白 Caspase-3 白血病 Vitamin E succinate Multidrug resistance apoptosis resistance P-glycoprotein Caspase-3 Leukemia
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