Reversal of p-glycoprotein-mediated multidrug resistance by CJX1, an amlodipine derivative, in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells
Reversal of p-glycoprotein-mediated multidrug resistance by CJX1, an amlodipine derivative, in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells
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DOI：
10.1016/j.lfs.2004.12.050
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发表时间：
2005-09-16
期刊：
影响因子：
6.1
通讯作者：
Liu, GQ
中科院分区：
文献类型：
--
作者：
Ji, BS;He, L;Liu, GQ
P-糖蛋白介导的药物外排可产生多药耐药（MDR）表型，这与对癌症化疗的不良反应有关。开发安全、有效的MDR逆转剂是临床治疗的重要途径。本研究旨在观察CJX 1对K562/DOX细胞及其亲本细胞P-gp功能的抑制作用及P-gp介导的多药耐药的影响。采用流式细胞术检测细胞对罗丹明123（rhodamine123，Rb123）的摄取、蓄积和外排。通过测定MTT（3-（4，5-二甲基噻唑）-2，5-二苯基溴化四氮唑）还原和逆转倍数（RF）值来评价CJX1对阿霉素细胞毒性的影响。流式细胞仪检测DNA含量、细胞凋亡率和细胞周期分析。还通过测定多柔比星相关的MFI来评估多柔比星的细胞内蓄积。维拉帕米用作比较剂。CJX1能显著增加K562/DOX细胞对Rh123的摄取，减少Rh123的外排，而K562细胞则无此作用。P-gp功能抑制剂的抑制作用是可逆的，但从孵育培养基中去除2.5 μ M CJX 1后，其至少持续90分钟。CJX1可显著增强阿霉素诱导的细胞毒性、细胞凋亡和细胞周期紊乱。在不同浓度的CJX1存在下，多柔比星的细胞内积累增强。CJX1在体外对P-gp介导的MDR有较强的逆转作用，有望成为肿瘤化疗中有效的MDR逆转剂。(c)2005年爱思唯尔公司All rights reserved.
P-glycoprotein-mediated drug efflux can yield a multidrug resistance (MDR) phenotype that is associated with a poor response to cancer chemotherapy. Development of safe and effective MDR reversing agents is an important approach in the clinic. The aim of this study was to observe the effects of CJX1, an amlodipine derivative, on the inhibition of P-gp function and P-gp-mediated MDR in K562/DOX cells and parental K562 cells. Based on the flow cytometric technology, the uptake, accumulation and efflux of rhodamine123 (Rb123) were detected in these cells by measuring Rh 123 -associated mean fluorescence intensity (MFI). The effects of CJX1 on the doxorubicin cytotoxicity were evaluated by assaying for MTT (3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide) reduction and the reversal fold (RF) values. The DNA content, percentage of apoptosis and cell cycle analysis were monitored with flow cytometry. Intracellular accumulation of doxorubicin was also assessed by the determination of doxorubicin-associated MFI. Verapamil was employed as a comparative agent. Incubation of K562/DOX cells with CJXl caused a marked increase in uptake and a notable decrease in efflux of Rh123, No such results were found in parental K562 cells. The inhibitory effect of the agent of P-gp function was reversible, but it persisted at least for 90 min after removal of 2.5 mu M CJX1 from incubation medium. The doxorubicin-induced cytotoxicity, apoptosis and cell cycle perturbations were significantly potentiated by CJX1. The intracellular accumulation of doxorubicin was enhanced in the presence of various concentrations of CJX1. The CJX1 exhibited potent effects in vitro in the reversal of P-gp-mediated MDR, suggesting that the compound may become a candidate of effective MDR reversing agent in cancer chemotherapy. (c) 2005 Elsevier Inc. All rights reserved.