Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881.
Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881.
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DOI：
10.1016/j.bcp.2017.02.019
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发表时间：
2017-05-15
影响因子：
5.8
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Zhang YK;Zhang XY;Zhang GN;Wang YJ;Xu H;Zhang D;Shukla S;Liu L;Yang DH;Ambudkar SV;Chen ZS
乳腺癌耐药蛋白（BCRP）在肺癌中的表达与多药耐药（MDR）的发展相关，因此导致化疗反应较低。ZM323881是一种先前开发的选择性VEGFR-2抑制剂，在本研究中发现对bcrp介导的MDR具有抑制作用。ZM323881显著降低过表达bcrp的NCI-H460/MX20细胞中米托蒽醌和SN-38的细胞毒剂量。机制研究表明，ZM323881通过抑制BCRP介导的药物外排而起作用，导致BCRP底物在细胞内积聚。BCRP过表达细胞暴露于ZM323881后，BCRP的表达水平和定位模式未见明显变化。观察受刺激的钟形atp酶活性。分子对接表明，ZM323881与BCRP调节位点结合，通过100 ns分子动力学模拟验证其结合姿态稳定。总之，我们的研究结果表明ZM323881通过抑制bcrp的外排功能逆转了bcrp相关的MDR。这些发现可能有助于开发耐多药癌症治疗的联合化疗。
The expression of breast cancer resistant protein (BCRP) in lung cancer is correlated with development of multidrug resistance (MDR) and therefore leads to lower response to chemotherapy. ZM323881, a previously developed selective VEGFR-2 inhibitor, was found to have inhibitory effects on BCRP-mediated MDR in this investigation. ZM323881 significantly decreased the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing NCI-H460/MX20 cells. Mechanistic studies revealed that ZM323881 effected by inhibiting BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates. No significant alteration in the expression levels and localization pattern of BCRP was observed when BCRP-overexpressing cells were exposed to ZM323881. Stimulated bell-shaped ATPase activities were observed. Molecular docking suggested that ZM323881 binds to the modulator site of BCRP and the binding pose is stable validated by 100 ns molecular dynamic simulation. Overall, our results indicated that ZM323881 reversed BCRP-related MDR by inhibiting its efflux function. These findings might be useful in developing combination chemotherapy for MDR cancer treatment.
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影响因子：
--
作者：
Zhang YK;Zhang H;Zhang GN;Wang YJ;Kathawala RJ;Si R;Patel BA;Xu J;Chen ZS
通讯作者：
Chen ZS
影响因子：
2.8
作者：
Zhang, Yi;Lu, Jianguo
通讯作者：
Lu, Jianguo
影响因子：
5.7
作者：
Henrich, Curtis J.;Robey, Robert W.;McMahon, James B.
通讯作者：
McMahon, James B.
影响因子：
37.3
作者：
Barr MP;Gray SG;Gately K;Hams E;Fallon PG;Davies AM;Richard DJ;Pidgeon GP;O'Byrne KJ
通讯作者：
O'Byrne KJ
影响因子：
45.3
作者：
Breathnach, OS;Freidlin, B;Johnson, BE
通讯作者：
Johnson, BE