Shi Zhi, Tiwari Amit K, Shukla Suneet, Robey Robert W, Kim In-Wha, Parmar Smitaben, Bates Susan E, Si Qiu-Sheng, Goldblatt Curtis S, Abraham Ioana, Fu Li-Wu, Ambudkar Suresh V, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA.
Biochem Pharmacol. 2009 Mar 1;77(5):781-93. doi: 10.1016/j.bcp.2008.11.007. Epub 2008 Nov 18.
The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific EGFR tyrosine kinase inhibitor (TKI); its promising pre-clinical results have led to clinical trials. Overexpression of ATP-binding cassette (ABC) transporters such as ABCB1, ABCC1 and ABCG2 is one of the main causes of multidrug resistance (MDR) and usually results in the failure of cancer chemotherapy. However, the interaction of AG1478 with these ABC transporters is still unclear. In the present study, we have investigated this interaction and found that AG1478 has differential effects on these transporters. In ABCB1-overexpressing cells, non-toxic doses of AG1478 were found to partially inhibit resistance to ABCB1 substrate anticancer drugs as well as increase intracellular accumulation of [3H]-paclitaxel. Similarly, in ABCG2-overexpressing cells, AG1478 significantly reversed resistance to ABCG2 substrate anticancer drugs and increased intracellular accumulation of [3H]-mitoxantrone as well as fluorescent compound BODIPY-prazosin. AG1478 also profoundly inhibited the transport of [3H]-E(2)17betaG and [3H]-methotrexate by ABCG2. We also found that AG1478 slightly stimulated ABCB1 ATPase activity and significantly stimulated ABCG2 ATPase activity. Interestingly, AG1478 did not inhibit the photolabeling of ABCB1 or ABCG2 with [125I]-iodoarylazidoprazosin. Additionally, AG1478 did not alter the sensitivity of parental, ABCB1- or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drug and had no effect on the function of ABCC1. Overall, we conclude that AG1478 is able to inhibit the function of ABCB1 and ABCG2, with a more pronounced effect on ABCG2. Our findings provide valuable contributions to the development of safer and more effective EGFR TKIs for use as anticancer agents in the clinic.
tyrphostin 4-(3-氯苯胺基)-6,7-二甲氧基喹唑啉（AG1478）是一种强效且特异性的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）；其在临床前研究中取得的良好结果已推动了临床试验的开展。ATP结合盒（ABC）转运蛋白如ABCB1、ABCC1和ABCG2的过表达是多药耐药（MDR）的主要原因之一，通常会导致癌症化疗失败。然而，AG1478与这些ABC转运蛋白之间的相互作用仍不清楚。在本研究中，我们对这种相互作用进行了研究，发现AG1478对这些转运蛋白具有不同的影响。在ABCB1过表达的细胞中，发现无毒剂量的AG1478可部分抑制对ABCB1底物抗癌药物的耐药性，并增加[3H] - 紫杉醇在细胞内的蓄积。同样，在ABCG2过表达的细胞中，AG1478可显著逆转对ABCG2底物抗癌药物的耐药性，并增加[3H] - 米托蒽醌以及荧光化合物BODIPY - 哌唑嗪在细胞内的蓄积。AG1478还可显著抑制ABCG2对[3H] - E(2)17βG和[3H] - 甲氨蝶呤的转运。我们还发现AG1478可轻微刺激ABCB1的ATP酶活性，并显著刺激ABCG2的ATP酶活性。有趣的是，AG1478不会抑制[125I] - 碘芳基叠氮哌唑嗪对ABCB1或ABCG2的光标记作用。此外，AG1478不会改变亲本细胞、ABCB1或ABCG2过表达细胞对非ABCB1和非ABCG2底物药物的敏感性，且对ABCC1的功能没有影响。总体而言，我们得出结论，AG1478能够抑制ABCB1和ABCG2的功能，对ABCG2的作用更为显著。我们的研究结果为开发更安全、更有效的EGFR TKIs作为临床抗癌药物提供了有价值的贡献。
