Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo.
Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo.
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DOI：
10.1002/ijc.27649
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发表时间：
2013-01-01
影响因子：
6.4
通讯作者：
Fu, Li-Wu
中科院分区：
文献类型：
--
作者：
Liu, Ke-Jun;He, Jie-Hua;Su, Xiao-Dong;Sim, Hong-May;Xie, Jing-Dun;Chen, Xing-Gui;Wang, Fang;Liang, Yong-Ju;Singh, Satyakam;Sodani, Kamlesh;Talele, Tanaji T.;Ambudkar, Suresh V.;Chen, Zhe-Sheng;Wu, Hai-Ying;Fu, Li-Wu
关键词：
Saracatinib 是一种高选择性 Src/Abl 双重激酶抑制剂，目前正在进行治疗卵巢癌的 II 期临床试验。在这项研究中，我们在体外和体内研究了萨拉卡替尼对逆转 ATP 结合盒 (ABC) 转运蛋白诱导的多药耐药性 (MDR) 的影响。结果表明，saracatinib显着增强ABCB1底物药物在ABCB1过表达HeLa/v200、MCF-7/adr和HEK293/ABCB1细胞中的细胞毒性，作用强于吉非替尼，而对ABCC1过表达HL-60/adr细胞及其亲本敏感细胞中底物的细胞毒性没有影响。此外，saracatinib 显着增加 HeLa/v200 和 MCF-7/adr 细胞中 Dox 和 Rho 123 的积累，而对 HeLa 和 MCF-7 细胞没有影响。此外，saracatinib 可刺激 ATP 酶活性，并以浓度依赖性方式抑制 [125I]-碘芳基叠氮哌唑嗪对 ABCB1 的光标记。此外，同源模型预测了 saracatinib 在人 ABCB1 的大疏水性药物结合腔内的结合构象。然而，在萨拉卡替尼的逆转浓度下，ABCB1 的表达水平和 Akt 的磷酸化水平均未改变。重要的是，saracatinib 显着增强了紫杉醇对裸鼠中 ABCB1 过表达 HeLa/v200 癌细胞异种移植物的作用。总之，saracatinib 通过直接抑制 ABCB1 转运功能，在体外和体内逆转 ABCB1 介导的 MDR，而不改变 ABCB1 表达或 AKT 磷酸化。这些发现可能有助于临床上将萨拉卡替尼与其他化疗药物联合使用来减弱MDR的影响。
Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a phase II clinical trial for the treatment of ovarian cancer. In this study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the Dox and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, while it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic.
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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：
5.6
作者：
Halgren, Thomas A.
通讯作者：
Halgren, Thomas A.
从咪唑衍生物中筛选新型、有效的多重耐药调节剂。
影响因子：
3.1
作者：
Chen, LM;Wu, XP;Fu, LW
通讯作者：
Fu, LW
影响因子：
3
作者：
Fu, LW;Liang, YJ;Pan, QC
通讯作者：
Pan, QC
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G