Functional characterization of gefitinib uptake in non-small cell lung cancer cell lines
Functional characterization of gefitinib uptake in non-small cell lung cancer cell lines
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DOI：
10.1016/j.bcp.2010.03.033
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发表时间：
2010-07-15
影响因子：
5.8
通讯作者：
Petronini, Pier Giorgio
中科院分区：
文献类型：
--
作者：
Galetti, Maricla;Alfieri, Roberta R.;Petronini, Pier Giorgio
吉非替尼是一种表皮生长因子受体酪氨酸激酶抑制剂，已被开发并批准用于治疗晚期非小细胞肺癌（NSCLC）。在这项研究中，我们研究了吉非替尼在吉非替尼敏感和耐药的非小细胞肺癌细胞系中的摄取情况。运输系统是温度依赖的，表明一个活跃的过程和钠和电位无关。此外，高细胞密度和低细胞外pH值显著降低了吉非替尼的摄取。人有机阳离子转运蛋白1 （hOCT1）抑制剂显著降低吉非替尼的摄取；然而，吉非替尼在过表达的HEK293细胞中不是hOCT1或hOCT2的底物。有趣的是，吉非替尼显著降低了hOCT原型底物MPP的摄取，这表明吉非替尼可能对hOCT1和hOCT2运输的药物在细胞内的积累有抑制作用。在1 μ M（临床相关剂量下获得的吉非替尼最大血浆浓度）治疗15分钟后，吉非替尼在耐药细胞系的细胞内积累，浓度与吉非替尼敏感细胞相似甚至更高，倾向于排除药物摄取改变作为吉非替尼治疗耐药机制的可能性。此外，我们的研究结果表明，拥挤的细胞挤压乳酸可能有助于降低pH值，从而影响吉非尼布的摄取，从而抑制EGFR自磷酸化。(C) 2010爱思唯尔公司版权所有。
Gefitinib, an inhibitor of epidermal growth factor receptor tyrosine kinase, has been developed and approved for treatment of advanced non-small cell lung cancer (NSCLC).In this study, we investigated the uptake of gefitinib in gefitinib-sensitive and -resistant NSCLC cell lines. The transport system was temperature-dependent, indicative of an active process and sodium- and potential-independent. Moreover, high cell densities and low extracellular pH significantly reduced the uptake of gefitinib. Inhibitors of the human organic cation transporter 1 (hOCT1) significantly decreased gefitinib uptake; however, gefitinib was not a substrate for hOCT1 or hOCT2 in overexpressing HEK293 cells. Interestingly, gefitinib significantly reduced uptake of the hOCT prototypical substrate MPP suggesting that gefitinib may exert an inhibitory effect on the intracellular accumulation of drugs transported by hOCT1 and hOCT2.After 15 min of treatment at 1 mu M (the maximum plasma concentration of gefitinib obtained at the clinically relevant dose) gefitinib accumulated within the cell in resistant-cell lines at concentrations similar or even higher than in gefitinib-sensitive cells tending to rule out an alteration in drug uptake as a mechanism of resistance to gefitinib treatment.Moreover, our results suggest that the extrusion of lactate by crowded cells may contribute in decreasing the pH, which in turn can influence the uptake of gefinitib and as a result the inhibition of EGFR autophosphorylation. (C) 2010 Elsevier Inc. All rights reserved.