The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance
The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance
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DOI：
10.3892/or_00000248
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发表时间：
2009-02-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Zhe-Sheng
中科院分区：
文献类型：
--
作者：
Shi, Zhi;Parmar, Smitaben;Chen, Zhe-Sheng
ABCG2是三磷酸腺苷结合盒(ABC)转运蛋白的重要成员，被发现与癌细胞的耐药有关。最近的研究表明，表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)吉非替尼能够调节ABCG2的功能，逆转ABCG2介导的癌细胞多药耐药(MDR)。此外，ABCG2的表达已被证明影响接受Gefitinib治疗的患者的治疗效果和副作用的发展。然而，目前还不清楚其他EGFR TKI是否以类似的方式与ABCG2相互作用。在本研究中，我们研究了另外两个EGFR TKI，AG1478和erlotinib与ABCG2的相互作用。我们的数据显示，AG1478和厄洛替尼对ABCG2底物抗癌药物黄烷醇和米托蒽醌有效地敏化过表达野生型或突变型ABCG2的耐药细胞。AG1478和erlotinib都没有使ABCG2过表达的细胞对非ABCG2底物的药物敏感，也没有影响亲本细胞的药物敏感性。此外，AG1478和厄洛替尼能够显著增加表达野生型和突变型ABCG2的细胞内米托蒽醌的积累。此外，它们没有改变ABCG2过表达细胞中ABCG2的蛋白表达。综上所述，我们得出结论：AG1478和厄洛替尼通过直接抑制ABCG2过表达细胞中ABCG2的药物外排功能而有效逆转ABCG2介导的多药耐药。这些结果将有助于开发新的和更有效的EGFR TKI以及开发联合化疗策略。
ABCG2 is an important member of ATP-binding cassette (ABC) transporter shown to confer drug resistance in cancer cells. Recent studies show that an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, is able to modulate the function of ABCG2 and reverse ABCG2-mediated multidrug resistance (MDR) in cancer cells. Additionally, ABCG2 expression has been shown to impact treatment efficacy and development of side-effects in patients receiving gefitinib. However, it is unclear whether other EGFR TKIs interact with ABCG2 in a similar manner. In the present study, we investigated the interaction of two other EGFR TKIs, AG1478 and erlotinib, with ABCG2. Our data show that AG1478 and erlotinib potently sensitized drug-resistant cells overexpressing either wild-type or mutated ABCG2 to the ABCG2 substrate anti-cancer drugs flavopiridol and mitoxantrone. Neither AG1478 nor erlotinib sensitized ABCG2-overexpressing cells to drugs that are not substrates of ABCG2 nor did they impact drug sensitivity of parental cells. Furthermore, AG1478 and erlotinib were able to significantly enhance the intracellular accumulation of mitoxantrone in cells expressing either wildtype or mutated ABCG2. Additionally, they did not alter the protein expression of ABCG2 in the ABCG2-overexpressing cells. Taken together, we conclude that AG1478 and erlotinib potently reverse ABCG2-mediated MDR through directly inhibiting the drug efflux function of ABCG2 in the ABCG2-overexpressing cells. These results will be useful in the development of novel and more effective EGFR TKIs as well as the development of combinational chemotherapeutic strategies.