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Action mechanism and clinical application of leukotriene receptor antagonist as multidrug resistance protein 1 (MRP1) modulator

白三烯受体拮抗剂作为多药耐药蛋白1（MRP1）调节剂的作用机制及临床应用

基本信息

批准号：
21790978
负责人：
OZEKI Michio
金额：
$ 2.66万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

项目摘要

Our purpose of research is to clarify the mechanism of anticancer drug resistance by tumor cells and developing effective resistance modulators. Multidrug resistance can be mediated by overexpression of the multidrug resistance protein 1(MRP1). MRP function as transmembrane efflux pumps, which decrease intracellular drug accumulation, thereby conferring multidrug resistance. One of the ways to overcome MRP1 mediated multidrug resistance is to use an inhibitor to block the function of MRP1. This is called MRP1 modulator. To date, several MRP1 modulator have entered study and clinical trials. Recently, leukotriene receptor antagonist(LTRA) is thought to be one of the MRP1 modulator. We studied effect to overcome drug resistance by LTRA and have developed original candidate medications.In our study duration, we got results as below; The resistance cancer cells was established by two methods. The cells were selected from Jurkat (human leukemia cell line) by chronic exposure to doxorubicin over 2 months and transfection of MRP1cDNA. In the resistant cells, the overexpression of MRP1 resulted from an increased MRPmRNA level transcribed from amplified MRP gene. The dose-response effects of LTRA in the presence or absence of doxorubicin were examined in both drug-sensitive Jurkat and MRP-overexpressing resistant cells. LTRA reversed Jurkat resistance. The fluorescent accumulation analysis revealed a significant increase of fluorescence in resistant Jurkat pre-incubated LTRA. We demonstrated that LTRA modulate MRP1 scientifically by the measurement of intracellular glutathione, ATPase assay, analysis of cell-cycle pathway. We have written the report now.

我们的研究目的是阐明肿瘤细胞的耐药机制，开发有效的耐药调节剂。多药耐药可通过多药耐药蛋白1（MRP1）的过表达介导。MRP作为跨膜外排泵，减少细胞内药物积累，从而产生多药耐药。克服MRP1介导的多药耐药的方法之一是使用抑制剂阻断MRP1的功能。这叫做MRP1调制器。迄今为止，已有几种MRP1调节剂进入研究和临床试验阶段。近年来，白三烯受体拮抗剂（LTRA）被认为是MRP1的调节剂之一。我们对LTRA的耐药效果进行了研究，并开发了原始的候选药物。在我们的研究期间，我们得到的结果如下：通过两种方法建立了耐药癌细胞。通过长期暴露于阿霉素2个月以上并转染MRP1cDNA，从Jurkat（人白血病细胞系）中选择细胞。在耐药细胞中，MRP1的过表达是由于MRP基因扩增后转录的MRPmRNA水平升高。在药物敏感的Jurkat和mrp过表达的耐药细胞中，研究了LTRA在阿霉素存在或不存在时的剂量反应效应。LTRA逆转了Jurkat的抵抗。荧光积累分析显示，抗性Jurkat预孵育LTRA的荧光显著增加。我们通过细胞内谷胱甘肽测定、atp酶测定、细胞周期途径分析，证明了LTRA对MRP1的调节是科学的。我们现在已经写好报告了。