Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine.
Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine.
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DOI：
10.1186/2193-1801-3-732
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Peters GJ
中科院分区：
文献类型：
--
作者：
Adema AD;Floor K;Smid K;Honeywell RJ;Scheffer GL;Jansen G;Peters GJ
我们的目的是确定多药耐药蛋白MRP 4（ABCC 4）和MRP 5（ABCC 5）是否赋予抗代谢药阿糖胞苷（Ara-C），吉西他滨（GEM）和L-核苷类似物曲沙他滨的耐药性。为此，我们使用HEK 293和转染的HEK/MRP 4（MRP 4增加59倍）或HEK/MRP 5i（MRP 5增加991倍）作为模型系统，并使用增殖试验测试细胞的药物敏感性。通过使用放射性Ara-C进行药物蓄积，并且对于GEM和曲沙他滨，使用HPLC串联-MS或UV检测。在4小时暴露时，HEK/MRP 4细胞对曲沙他滨、ara-C和9-（2-膦酰基甲氧基乙基）腺嘌呤（PMEA）具有2-4倍抗性，HEK/MRP 5i对ara-C和PMEA具有2 - 4倍抗性，但对GEM无抗性。抑制剂丙磺舒和吲哚美辛逆转耐药性。暴露4小时后，MRP 4/5细胞中的ara-C-核苷酸降低2-3倍，其中用无药物培养基（DFM）洗涤后它们下降得更快。3种细胞系中的曲卡他滨蓄积相似，但在DFM期后，MRP 4/5细胞中的曲卡他滨降低快2-4倍。曲沙他滨核苷酸在MRP 4/5细胞中降低约25%，在MRP 4中迅速降低，但在MRP 5细胞中不降低。在MRP 4/5细胞中，GEM-核苷酸的积累更高。最后：MRP 4和MRP 5过表达赋予对曲沙他滨和阿糖胞苷的抗性，但不赋予对GEM的抗性，这与HEK/MRP 4 -5细胞中阿糖胞苷和曲沙他滨核苷酸的快速下降相关。本文的在线版本（doi：10.1186/2193-1801-3-732）包含补充材料，可供授权用户使用。
We aimed to determine whether the multidrug-resistance-proteins MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the antimetabolites cytarabine (Ara-C), gemcitabine (GEM), and the L-nucleoside analog troxacitabine. For this purpose we used HEK293 and the transfected HEK/MRP4 (59-fold increased MRP4) or HEK/MRP5i (991-fold increased MRP5) as model systems and tested the cells for drug sensitivity using a proliferation test. Drug accumulation was performed by using radioactive Ara-C, and for GEM and troxacitabine with HPLC with tandem-MS or UV detection. At 4-hr exposure HEK/MRP4 cells were 2-4-fold resistant to troxacitabine, ara-C and 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and HEK/MRP5i to ara-C and PMEA, but none to GEM. The inhibitors probenecid and indomethacin reversed resistance. After 4-hr exposure ara-C-nucleotides were 2-3-fold lower in MRP4/5 cells, in which they decreased more rapidly after washing with drug-free medium (DFM). Trocacitabine accumulation was similar in the 3 cell lines, but after the DFM period troxacitabine decreased 2-4-fold faster in MRP4/5 cells. Troxacitabine-nucleotides were about 25% lower in MRP4/5 cells and decreased rapidly in MRP4, but not in MRP5 cells. Accumulation of GEM-nucleotides was higher in the MRP4/5 cells. In conclusion: MRP4 and MRP5 overexpression confer resistance to troxacitabine and ara-C, but not to GEM, which was associated with a rapid decline of the ara-C and troxacitabine-nucleotides in HEK/MRP4-5 cells. The online version of this article (doi:10.1186/2193-1801-3-732) contains supplementary material, which is available to authorized users.
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影响因子：
10.9
作者：
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通讯作者：
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影响因子：
3.4
作者：
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Peters, Godefridus J.