Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells
Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells
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DOI：
10.1007/s00204-012-0956-6
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发表时间：
2013-06
影响因子：
6.1
通讯作者：
S. Xu;Yan Fang;Zhang bullet;M. Carew;Wen Hui;Hao bullet;Jacky Fong;Chuen Loo;Hua Naranmandura;bullet X Chris Le
中科院分区：
文献类型：
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作者：
S. Xu;Yan Fang;Zhang bullet;M. Carew;Wen Hui;Hao bullet;Jacky Fong;Chuen Loo;Hua Naranmandura;bullet X Chris Le
三氧化二砷（As2O3）是治疗急性早幼粒细胞白血病以及其他类型恶性肿瘤最有效的药物之一。然而，HL-60细胞对As2O3具有耐药性，而As2O3及其生物甲基化产物，即单甲基larsonous酸（MMAIII）治疗肿瘤的潜在耐药机制尚不清楚。在本研究中，我们研究了iasiii及其中间代谢物mmaiii在HL-60细胞中诱导抗癌作用的分子机制。在这里，我们发现HL-60细胞对无机iAsIII（IC50= 10 μM）表现出抗性，但对其中间体MMAIII（IC50= 3.5 μM）相对敏感。此外，我们发现在HL-60细胞中表达多药耐药蛋白1 (MRP1)，而不是MRP2，这减少了细胞内砷的积累，并赋予了对无机iasiii和MMAIII的抗性。MRP1抑制剂MK571预处理HL-60可显著增加iasiii和mmaiii诱导的细胞毒性和砷积累，提示MRP1/4的表达可能导致HL-60细胞对三价砷化合物产生抗性。
Arsenic trioxide (As2O3) is established as one of the most effective drugs for treatment of patients with acute promyelocytic leukemia, as well as other types of malignant tumors. However, HL-60 cells are resistant to As2O3, and little is known about the underlying resistance mechanism for As2O3and its biomethylation products, namely, monomethylarsonous acid (MMAIII) on the treatment of tumors. In the present study, we investigated the molecular mechanisms underlying iAsIIIand its intermediate metabolite MMAIII-induced anticancer effects in the HL-60 cells. Here, we show that the HL-60 cells exhibit resistance to inorganic iAsIII(IC50= 10 μM), but are relatively sensitive to its intermediate MMAIII(IC50= 3.5 μM). Moreover, we found that the multidrug resistance protein 1 (MRP1), but not MRP2, is expressed in HL-60 cells, which reduced the intracellular arsenic accumulation, and conferred resistance to inorganic iAsIIIand MMAIII. Pretreatment of HL-60 with MK571, an inhibitor of MRP1, significantly increased iAsIIIand MMAIII-induced cytotoxicity and arsenic accumulations, suggesting that the expression of MRP1/4 may lead to HL-60 cells resistance to trivalent arsenic compounds.