Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro
Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro
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DOI：
10.1158/0008-5472.can-03-3344
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发表时间：
2004-04-01
期刊：
影响因子：
11.2
通讯作者：
Traxler, P
中科院分区：
文献类型：
--
作者：
Houghton, PJ;Germain, GS;Traxler, P
甲磺酸伊马替尼(Gleevec，ST1571)是一种对bcr-Abl、活化的c-Kit激酶和血小板衍生生长因子受体酪氨酸激酶具有选择性的激酶抑制剂。甲磺酸伊马替尼类似于许多其他酪氨酸激酶抑制剂(TKI)，如4-苯胺喹唑啉类成员，竞争与ATP的结合。此前，4-苯胺喹唑啉TKI已被证明可以抑制乳腺癌耐药相关药物转运体(ABCG2)的功能，逆转对喜树碱衍生物Topotecan和SN-38的耐药性。然而，以甲磺酸伊马替尼为例，对2-苯氨基-嘧啶类TKI的ABCG2抑制作用的潜力尚未被检测。在这里，我们表明，甲磺酸伊马替尼有效地逆转了ABCG2介导的对拓扑替康和SN-38的耐药性，并显著增加了拓扑替康仅在表达功能性ABCG2的细胞中的积累。然而，ABCG2的过表达并不会对甲磺酸伊马替尼产生耐药性。此外，[C-14]甲磺酸伊马替尼在表达ABCG2和不表达ABCG2的细胞之间的累积和外流没有变化，也不受ATP耗尽的影响。这些结果表明，甲磺酸伊马替尼抑制ABCG2的功能，但不是该转运蛋白的底物。
Imatinib mesylate (Gleevec, ST1571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [C-14]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.