Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters.
Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters.
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DOI：
10.1158/0008-5472.can-10-0111
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Fu LW
中科院分区：
文献类型：
--
作者：
Mi YJ;Liang YJ;Huang HB;Zhao HY;Wu CP;Wang F;Tao LY;Zhang CZ;Dai CL;Tiwari AK;Ma XX;To KK;Ambudkar SV;Chen ZS;Fu LW
阿帕替尼是一种小分子多靶点酪氨酸激酶抑制剂，目前正在中国进行治疗非小细胞肺癌和胃癌患者的III期临床试验。在这项研究中，我们确定了阿帕替尼对特异性抗肿瘤化合物与P-糖蛋白（P-gp，ABCB 1）、多药耐药蛋白1（MRP 1，ABCC 1）和乳腺癌耐药蛋白（BCRP，ABCG 2）相互作用的影响。我们的结果表明，阿帕替尼显著增强了ABCB 1或ABCG 2底物药物在过表达ABCB 1和S1-M1-80的KBv 200、MCF-7/adr和HEK 293/ABCB 1细胞、过表达ABCG 2（野生型）的MCF-7/FLV 1000和HEK 293/ABCG 2-R2细胞中的细胞毒性。相比之下，阿帕替尼没有改变亲本细胞和过表达ABCC 1的细胞中特定底物的细胞毒性。阿帕替尼显著增加了多药耐药（MDR）细胞中罗丹明123和阿霉素的细胞内蓄积。此外，阿帕替尼以浓度依赖性方式显著抑制ABCB 1和ABCG 2与[125 I]-碘芳基叠氮吡唑嗪的光标记。阿帕替尼可显著增加ABCB 1和ABCG 2的ATP酶活性。然而，在产生MDRl逆转的浓度下，阿帕替尼没有显著改变ABCB 1或ABCG 2蛋白或mRNA水平的表达或AKT和ERK 1/2的磷酸化。重要的是，阿帕替尼显著增强了紫杉醇对裸鼠中ABCB 1耐药KBv 200癌细胞异种移植物的作用。总之，阿帕替尼通过抑制其转运功能逆转ABCB 1和ABCG 2介导的MDR，而不是通过阻断AKT或ERK 1/2通路或下调ABCB 1或ABCG 2表达。阿帕替尼可能有助于规避其他常规化疗药物的MDR。
Apatinib, a small-molecule multi-targeted tyrosine kinase inhibitor, is in phase III clinical trial for treatment of patients with non-small cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (P-gp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr and HEK293/ABCB1 cells overexpressing ABCB1 and S1-M1-80, MCF-7/FLV1000 and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photolabeling of both ABCB1 and ABCG2 with [125I]-iodoarylazidoprazosin in a concentration-dependent fashion. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration the produced a reversal of MDRl, did not significantly alter the expression of the ABCB1 or ABCG2 protein or mRNA levels or the phosphorylation of AKT and ERK1/2. Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1 resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs.