Differential expression and response to arsenic stress of MRPs and ASAN1 determine sensitivity of classical multidrug-resistant leukemia cells to arsenic trioxide
Differential expression and response to arsenic stress of MRPs and ASAN1 determine sensitivity of classical multidrug-resistant leukemia cells to arsenic trioxide
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DOI：
10.1016/j.leukres.2016.10.003
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发表时间：
2016-11-01
影响因子：
2.7
通讯作者：
Wei, Hulai
中科院分区：
文献类型：
--
作者：
Chen, Jing;Cheng, Jie;Wei, Hulai
三氧化二砷与传统化疗药物之间不存在交叉耐药性。经典的多药耐药(MDR)细胞对三氧化二砷仍然敏感，甚至可能逆转耐药性。三氧化二砷对白血病/肿瘤也有效，尽管传统的细胞毒性药物或靶向药物仍存在。通过对白血病HL-60细胞进行阿霉素筛选，我们获得了一株高度耐砷的多药耐药白血病细胞株HL-60/RS。我们比较了成对亲本/耐砷HL-60/RS/HL-60细胞和砷敏感/亲本K562/ADM/K562细胞对砷的敏感性，以及与砷相关的转运蛋白MRP1、MRP2和ASNA1的表达和对砷的反应。MRP1、MRP2和ASNA1的表达水平与细胞对三氧化二砷的敏感性呈负相关，其中ASNA1在HL-60/RS细胞中的表达最高，在K562/ADM细胞中最低。与亲本敏感细胞相比，三氧化二砷可显著上调HL-60/RS细胞MRP1、MRP2和ASNA1的表达水平，抑制K562/ADM细胞MRP1、MRP2和ASNA1的表达，符合HL-60/RS细胞的高耐药性和K562/ADM细胞的高敏感性。总之，传统化疗药物耐药的白血病细胞对三氧化二砷的交叉耐药性取决于MRP1、MRP2和ASNA1的水平，也取决于这些转运体对砷胁迫的反应。(C)2016爱思唯尔有限公司。保留所有权利。
There is no cross-resistance between arsenic trioxide and conventional chemotherapeutics. Classical multi-drug resistant (MDR) cells remain sensitive to arsenic trioxide, which may even reverse the drug resistance. Arsenic trioxide is also effective in leukemias/tumors that persist despite conventional cytotoxic or targeted drugs. We obtained a highly arsenic-resistant MDR leukemic cell line, HL-60/RS, by exposing leukemic HL-60 cells to adriamycin selection. We compared the arsenic sensitivity, and the expression and responses to arsenic of the arsenic-related transporters, MRP1, MRP2, and ASNA1, in paired parent/arsenic-resistant HL-60/RS/HL-60 and arsenic-sensitive/parental K562/ADM/K562 cells. Expression levels of MRP1, MRP2, and ASNA1 were negatively correlated with cell sensitivities to arsenic trioxide, and ASNA1 expression notably was highest in HL-60/RS cells and lowest in K562/ADM cells. Expression levels of MRP1, MRP2, and ASNA1 were significantly enhanced in HL-60/RS cells and inhibited in K562/ADM cells by arsenic trioxide treatment, compared with their parental sensitive cells, in accord with the high-resistance of HL-60/RS cells and high-sensitivity of K562/ADM cells. In conclusion, the cross-resistance of conventional chemotherapeutics-resistant leukemic cells to arsenic trioxide is determined by both levels of MRP1, MRP2, and ASNA1, and also by the responses of these transporters to arsenic stress. (C) 2016 Elsevier Ltd. All rights reserved.