三氧化二砷抑制K562/ADM细胞P-糖蛋白表达并提高化疗药物的敏感性  

Arsenic trioxide inhibits P-glycoprotein expression in multidrug-resistant human leukemia K562/ADM cell line that overexpresses mdr-1 gene and enhances their chemotherapeutic sensitivity

作　　者：魏虎来[1] 姚小健[2] 李宇宁[3] 王蓓[1] 赵怀顺[1] 白德成[1] 彭晓[2] 马兰芳[2] 

机构地区：[1]兰州医学院医学实验中心,730000 [2]兰州医学院血液病研究所 [3]兰州医学院第一附属医院

出　　处：《中华血液学杂志》2003年第1期28-31,共4页Chinese Journal of Hematology

基　　金：甘肃省中青年科技基金 (YS981 A2 3 0 10 );甘肃省培养造就跨世纪学术技术带头人专项基金 (G3KZ 2031)资助项目

摘　　要：目的　研究三氧化二砷 (As2 O3 )对人多药耐药白血病细胞K5 6 2 ADM的诱导凋亡作用和对P 糖蛋白 (P gp)表达及功能的影响 ,以及As2 O3 与常规化疗药物对耐药细胞的联合效应。方法　以白血病多药耐药细胞系K5 6 2 ADM为As2 O3 作用的靶细胞 ,用MTT比色法检测细胞增殖活性 ,光镜、激光共聚焦显微镜和电镜观察形态学变化 ,流式细胞术进行细胞周期分析和P gp表达的检测 ,激光共聚焦显微镜检测P gp功能。结果　K5 6 2 ADM细胞对阿霉素 (ADM)高度耐受 ,并与柔红霉素 (DNR)和足叶乙甙 (Vp16 )交叉耐药。 0 .5～ 2 0 .0 μmol LAs2 O3 抑制K5 6 2 ADM细胞增殖 ,抑制活性高于K5 6 2细胞。经As2 O3 诱导后K5 6 2 ADM细胞出现典型的凋亡形态学变化和亚G1 期细胞比例增高等凋亡特征性改变。As2 O3 下调K5 6 2 ADM细胞P gp的表达并抑制其功能 ,增加K5 6 2 ADM细胞对ADM、DNR和Vp16的敏感性。结论　As2 O3 能够诱导白血病多药耐药细胞凋亡 ,并通过抑制耐药细胞P gp的表达和功能提高耐药白血病细胞对常规化疗药物的敏感性。Objective To investigate the effects of arsenic trioxide (As 2O 3) on the apoptosis and P-glyco-protein (P-gp) expression of multidrug-resistant human leukemia K562/ADM cells, and the combined effects of As 2O 3 with conventional chemotherapeutic agents. Methods Multidrug-resistant human leukemia cell line K562/ADM that overexpresses mdr-1 gene was used as the target cells. The cell proliferating activity was assessed with a MTT assay. Cell morphology was examined by light microscopy, confocal microscopy and electron-microscopy. P-gp expression, cell-cycle status were determined by flow cytometry. Results K562/ADM cells were highly resistant to adriamycin, and cross-resistant to daunorubicin and etoposide. As 2O 3 at concentrations of 0.5 to 20 μmol/L inhibited the proliferation of K562/ADM cells, and K562/ADM cells were more sensitive to As 2O 3 than their parent K562 cells did. As 2O 3 induced marked apoptosis of K562/ADM cells showed by typical apoptotic morphological changes and the appearance of high sub-G 1 cell population. As 2O 3 significantly inhibited the P-gp expression in K562/ADM cells, and exerted a synergistic effect on the enhancement of the cell sensitivity to adriamycin, daunorubicin and etoposide. Conclusion As 2O 3 induces growth-inhibition and apoptosis of multidrug-resistant K562/ADM cells, and augments synergistically the sensitivity of the cells to conventional chemotherapeutic agents via down-regulation of P-gp expression.

关 键 词：三氧化二砷 砷剂 药物疗法 P糖蛋白 细胞凋亡 药物协同作用 白血病 

分 类 号：R73-36[医药卫生—肿瘤]