Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10).
Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10).
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DOI：
10.3892/or.2013.2362
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发表时间：
2013-06
期刊：
影响因子：
4.2
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Deng W;Dai CL;Chen JJ;Kathawala RJ;Sun YL;Chen HF;Fu LW;Chen ZS
atp结合盒（ABC）转运体介导的多药耐药（MDR）是引起肿瘤细胞对抗肿瘤药物耐药的主要机制之一。ABC转运蛋白可以通过增加抗肿瘤药物的外排来显著降低细胞内抗肿瘤药物的浓度，从而降低抗肿瘤药物的细胞毒性活性。其中一种转运体，多药耐药蛋白7 (MRP7/ABCC10)，已经被证明可以通过增加药物的外排来产生对抗肿瘤药物的耐药性。在本研究中，我们研究了坦都替尼，一种fms样酪氨酸激酶3 （FLT3）抑制剂，是否具有逆转mrp7介导的MDR的潜力。我们的研究结果显示，坦都替尼显著增强了MRP7转染的HEK293细胞对2种MRP7底物紫杉醇和新碱的敏感性，而对对照载体转染的HEK293细胞的影响较小或没有影响。[3H]-紫杉醇积累和流出研究表明，坦都替尼增加了[3H]-紫杉醇在HEK-MRP7细胞内的积累，抑制了[3H]-紫杉醇在HEK-MRP7细胞内的流出。此外，western blot分析显示，坦都替尼对MRP7的表达没有显著影响。因此，我们得出结论，FLT3抑制剂坦都替尼可以通过抑制药物外排功能逆转mrp7介导的MDR，可能具有临床应用于癌症患者联合治疗的潜力。
It is well established that ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) is one of the major mechanisms that causes resistance to antineoplastic drugs in cancer cells. ABC transporters can significantly decrease the intracellular concentration of antineoplastic drugs by increasing their efflux, thereby lowering their cytotoxic activity. One of these transporters, the multidrug resistance protein 7 (MRP7/ABCC10), has already been shown to produce resistance to antineoplastic drugs by increasing the efflux of the drugs. In the present study, we investigated whether tandutinib, an FMS-like tyrosine kinase 3 (FLT3) inhibitor, has the potential to reverse MRP7-mediated MDR. Our results revealed that tandutinib significantly enhanced the sensitivity of MRP7-transfected HEK293 cells to the 2 established MRP7 substrates, paclitaxel and vincristine, whereas there was less or no effect on the control vector-transfected HEK293 cells. [3H]-paclitaxel accumulation and efflux studies demonstrated that tandutinib increased the intracellular accumulation of [3H]-paclitaxel and inhibited the efflux of [3H]-paclitaxel from HEK-MRP7 cells. In addition, western blot analysis showed that tandutinib did not significantly affect MRP7 expression. Thus, we conclude that the FLT3 inhibitor tandutinib can reverse MRP7-mediated MDR through inhibition of the drug efflux function and may have potential to be used clinically in combination therapy for cancer patients.
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影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
30.8
作者：
Zhang, Haojian;Peng, Cong;Hu, Yiguo;Li, Huawei;Sheng, Zhi;Chen, Yaoyu;Sullivan, Con;Cerny, Jan;Hutchinson, Lloyd;Higgins, Anne;Miron, Patricia;Zhang, Xueqing;Brehm, Michael A.;Li, Dongguang;Green, Michael R.;Li, Shaoguang
通讯作者：
Li, Shaoguang
影响因子：
2.6
作者：
Bliss, CI
通讯作者：
Bliss, CI
影响因子：
20.3
作者：
DeAngelo, Daniel J.;Stone, Richard M.;Heinrich, Michael C.
通讯作者：
Heinrich, Michael C.
影响因子：
3.6
作者：
Chen, ZS;Hopper-Borge, E;Kruh, GD
通讯作者：
Kruh, GD