Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo.
Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo.
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DOI：
10.18632/oncotarget.2647
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Fu LW
中科院分区：
文献类型：
--
作者：
Wang XK;To KK;Huang LY;Xu JH;Yang K;Wang F;Huang ZC;Ye S;Fu LW
化疗药物的多药耐药（MDR）是癌症化疗成功的巨大障碍。atp结合盒（ABC）转运体的表达有助于临床MDR表型。本研究发现，靶向EGFR、HER-2和HER-4的小分子酪氨酸激酶抑制剂（TKI）阿法替尼（afatinib）在体外可逆转ABCG2介导的化疗耐药，但对多药耐药蛋白ABCB1和ABCC1介导的化疗耐药无影响。此外，阿法替尼联合拓扑替康在体内可显著抑制过表达abcg2的细胞异种移植物肿瘤的生长。机制研究表明，阿法替尼显著抑制ABCG2的atp酶活性，下调ABCG2的表达水平，从而抑制ABCG2的外排活性，同时增加ABCG2底物抗癌药物在细胞内的蓄积。综上所述，我们的研究结果可能为ABCG2过表达癌细胞患者提供一种新的、有用的阿法替尼联合化疗药物的联合治疗策略。
Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2-overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.
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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
DOI：
10.1186/bcr303
发表时间：
2001
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Li J;Xu LZ;He KL;Guo WJ;Zheng YH;Xia P;Chen Y
通讯作者：
Chen Y
影响因子：
3
作者：
Fu, LW;Liang, YJ;Pan, QC
通讯作者：
Pan, QC
影响因子：
11.4
作者：
Steinbach, D;Sell, W;Sauerbrey, A
通讯作者：
Sauerbrey, A
影响因子：
11.5
作者：
Benderra, Z;Faussat, AM;Legrand, O
通讯作者：
Legrand, O