Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters
Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters
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DOI：
10.1038/leu.2009.166
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发表时间：
2009-11-01
期刊：
影响因子：
11.4
通讯作者：
Mountford, J. C.
中科院分区：
文献类型：
--
作者：
Davies, A.;Jordanides, N. E.;Mountford, J. C.
甲磺酸伊马替尼和尼洛替尼在根除大多数慢性粒细胞白血病（CML）细胞方面非常有效;然而，这两种药物都不能诱导原始CML CD 34（+）细胞凋亡。一种可能的解释是，CD 34（+）细胞没有积累足够的细胞内药物水平，因为不充分的主动摄取或增加流出。为了确定尼洛替尼与主要临床相关药物转运蛋白的相互作用，我们在CML细胞系和原始（CD 34（+））原代CML细胞中分析了尼洛替尼与MDR 1（ABCB 1）、MRP 1（ABCC 1）、ABCG 2（BCRP）和人有机阳离子转运蛋白（hOCT）1的相互作用。尼洛替尼既不依赖于hOCT 1的主动输入，也不通过分析的ATP结合盒转运蛋白外排。事实上，我们发现尼洛替尼是hOCT 1、MDR 1和ABCG 2的抑制剂。外排转运蛋白MDR 1、MRP 1和ABCG 2在CML CD 34_细胞上的表达分别为对照的13.5%、108%和291%，尽管hOCT 1表达不存在;但是，外排转运蛋白活性抑制不会增强尼洛替尼对细胞凋亡、Bcr-Abl抑制或CML CD 34（+）细胞增殖的影响。因此，我们没有发现尼洛替尼通过hOCT 1主动摄取或通过MDR 1、MRP 1或ABCG 2外排的证据，因此这些转运蛋白不太可能对该药物的临床应答产生任何影响。Leukemia（2009）23，1999-2006; doi：10.1038/leu.2009.166; 2009年8月27日在线发表
Imatinib mesylate and nilotinib are highly effective at eradicating the majority of chronic myeloid leukemia (CML) cells; however, neither agent induces apoptosis of primitive CML CD34(+) cells. One possible explanation is that CD34(+) ells do not accumulate sufficient intracellular drug levels because of either inadequate active uptake or increased efflux. To determine the interaction of nilotinib with major clinically implicated drug transporters, we analyzed their interactions with MDR1 (ABCB1), MRP1 (ABCC1), ABCG2 (BCRP) and human organic cation transporter (hOCT) 1 in CML cell lines and primitive (CD34(+)) primary CML cells. Nilotinib is neither dependent on active import by hOCT1, nor effluxed through the ATP-binding cassette transporters analyzed. Indeed, we found nilotinib to be an inhibitor of hOCT1, MDR1 and ABCG2. The efflux transporters MDR1, MRP1 and ABCG2 are expressed on CML CD34_ cells at 13.5, 108 and 291% of control, respectively, although hOCT1 expression was absent; however, inhibition of efflux transporter activity did not potentiate the effect of nilotinib on apoptosis, Bcr-Abl inhibition or CML CD34(+) cell proliferation. Therefore, we have found no evidence for either active uptake of nilotinib through hOCT1 or efflux through MDR1, MRP1 or ABCG2, and it is therefore unlikely that these transporters will have any effect on the clinical response to this drug. Leukemia (2009) 23, 1999-2006; doi: 10.1038/leu.2009.166; published online 27 August 2009