Erlotinib (Tarceva, OSI-774) antagonizes ATP-bInding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance
Erlotinib (Tarceva, OSI-774) antagonizes ATP-bInding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance
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DOI：
10.1158/0008-5472.can-07-2686
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发表时间：
2007-11-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Zhe-Sheng
中科院分区：
文献类型：
--
作者：
Shi, Zhi;Peng, Xing-Xiang;Chen, Zhe-Sheng
据报道，吉非替尼是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），能够调节某些atp结合盒（ABC）转运体的功能，并能够逆转ABC亚家族B成员I （ABCB1； p糖蛋白）-和ABC亚家族G成员2 （ABCG2；乳腺癌耐药蛋白/米托蒽醌耐药蛋白）介导的癌细胞多药耐药（MDR）。然而，尚不清楚其他EGFR TKIs是否具有与吉非替尼相似的作用。在本研究中，我们研究了另一种EGFR TKI厄洛替尼与选定的ABC药物转运体的相互作用。我们的研究结果表明，厄洛替尼显著增强了已建立的ABCB1或ABCG2底物的敏感性，并增加了ABCB1或ABCG2过表达细胞中紫杉醇或米托蒽醌的积累。此外，厄洛替尼没有显著改变非abcb1或非abcg2底物在所有细胞中的敏感性，不能逆转mrp1介导的MDR，对亲代细胞没有影响。然而，厄洛替尼显著抑制ABCG2对E(2)17 β G和甲氨蝶呤的转运。此外，ATPase检测结果显示，厄洛替尼刺激ABCB1和ABCG2的ATPase活性。有趣的是，厄洛替尼在高浓度下对[1251]idoarylazidoprazosin （IAAP）对ABCB1的光标记有轻微抑制作用，但对ABCG2的LAAP光标记没有抑制作用。总之，我们得出结论，厄洛替尼通过直接抑制ABCB1和ABCG2的药物外排功能逆转ABCB1和ABCG2介导的癌细胞耐多药。这些发现可能对临床应用厄洛替尼联合治疗癌症有帮助。
It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member I (ABCB1; P-glycoprotein)- and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein) -mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1- or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E(2)17 beta G and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [1251] iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with LAAP. Overall, we conclude that erlotinib reverses ABCB1- and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic.