Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.
Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.
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DOI：
10.1158/0008-5472.can-08-0499
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发表时间：
2008-10-01
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：
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
拉帕替尼在与人表皮生长因子受体(EGFR，HER-1或ErbB1)和HER-2相关的酪氨酸激酶的ATP结合部位具有活性。可以想象的是，拉帕替尼可能通过结合ATP结合部位来抑制ATP结合盒(ABC)转运体的功能。本研究的目的是研究拉帕替尼逆转由于ABCB1和ABCG2转运蛋白过表达引起的肿瘤多药耐药(MDR)的能力。我们的结果表明，在表达这些转运蛋白的细胞中，拉帕替尼显著提高了对ABCB1或ABCG2底物的敏感性，尽管在亲代敏感的MCF-7或S1细胞中，拉帕替尼与常规化疗药物的联合使用观察到了轻微的协同效应。然而，单独使用拉帕替尼并不能显著改变敏感和耐药细胞中非ABCB1或非ABCG2底物的敏感性。此外，拉帕替尼显著增加阿霉素或米托蒽醌在ABCB1或ABCG2过表达细胞中的蓄积，并抑制ABCG2转运甲氨蝶呤和E217βG。此外，拉帕替尼还以浓度依赖的方式刺激ABCB1和ABCG2的ATPase活性，并抑制[125I][125I]碘代氮卓酮对ABCB1和ABCG2的光标记作用。然而，拉帕替尼不影响这些转运蛋白在mRNA或蛋白水平的表达。重要的是，拉帕替尼还增强了紫杉醇对ABCB1高表达的KBv200细胞裸鼠移植瘤生长的抑制作用。总之，我们得出结论，拉帕替尼通过直接抑制ABCB1和ABCG2的转运功能来逆转ABCB1和ABCG2介导的MDR。这些发现可能对临床应用拉帕替尼联合治疗癌症有一定的参考价值。
Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (EGFR, Her-1, or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABCB1 and ABCG2 transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1 or ABCG2 overexpressing cells and inhibited the transport of methotrexate and E217βG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [125I]Iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.