Gefitinib reverses breast cancer resistance protein-mediated drug resistance.
Gefitinib reverses breast cancer resistance protein-mediated drug resistance.
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DOI：
10.1158/1535-7163.1119.3.9
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发表时间：
2004-09
影响因子：
5.7
通讯作者：
Kae Yanase;Satomi Tsukahara;Sakiyo Asada;E. Ishikawa;Y. Imai;Y. Sugimoto
中科院分区：
文献类型：
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作者：
Kae Yanase;Satomi Tsukahara;Sakiyo Asada;E. Ishikawa;Y. Imai;Y. Sugimoto
乳腺癌耐药蛋白（BCRP）是一种ATP结合盒转运蛋白，对一系列抗癌药物如7-乙基-10-羟基喜树碱（SN-38）、拓扑替康和米托蒽醌具有耐药性。在这项研究中，我们评估了选择性表皮生长因子受体酪氨酸激酶抑制剂吉非替尼与BCRP可能的相互作用。BCRP转导的人表皮样癌A431 （A431/BCRP）细胞获得了对吉非替尼的细胞耐药，提示BCRP可能是某些细胞对吉非替尼敏感性的决定因素之一。接下来，研究吉非替尼对bcrp介导的耐药的影响。吉非替尼在BCRP转导的人髓性白血病K562 （K562/BCRP）或BCRP转导的小鼠淋巴细胞白血病P388 （P388/BCRP）细胞中逆转了SN-38耐药，但在这些亲本细胞中没有作用。此外，吉非替尼使内源性表达BCRP的人结肠癌HT-29细胞对SN-38敏感。吉非替尼增加了K562/BCRP细胞中拓扑替康的细胞内积累，抑制了K562/BCRP细胞膜泡中雌酮3-硫酸酯（BCRP的底物）的atp依赖性转运。这些结果提示吉非替尼可能通过抑制BCRP的泵功能来克服BCRP介导的耐药。此外，伊立替康和吉非替尼联合治疗的P388/ bcrp移植小鼠的存活时间明显长于伊立替康单独治疗或吉非替尼单独治疗的小鼠。总之，吉非替尼显示与BCRP相互作用。BCRP在某种细胞中的表达被认为是吉非替尼敏感性的决定因素之一。吉非替尼在体外和体内均抑制BCRP转运蛋白功能，逆转BCRP介导的耐药性。
Breast cancer resistance protein (BCRP) is an ATP binding cassette transporter that confers resistance to a series of anticancer agents such as 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, and mitoxantrone. In this study, we evaluated the possible interaction of gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, with BCRP. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) cells acquired cellular resistance to gefitinib, suggesting that BCRP could be one of the determinants of gefitinib sensitivity in a certain sort of cells. Next, the effect of gefitinib on BCRP-mediated drug resistance was examined. Gefitinib reversed SN-38 resistance in BCRP-transduced human myelogenous leukemia K562 (K562/BCRP) or BCRP-transduced murine lymphocytic leukemia P388 (P388/BCRP) cells but not in these parental cells. In addition, gefitinib sensitized human colon cancer HT-29 cells, which endogenously express BCRP, to SN-38. Gefitinib increased intracellular accumulation of topotecan in K562/BCRP cells and suppressed ATP-dependent transport of estrone 3-sulfate, a substrate of BCRP, in membrane vesicles from K562/BCRP cells. These results suggest that gefitinib may overcome BCRP-mediated drug resistance by inhibiting the pump function of BCRP. Furthermore, P388/BCRP-transplanted mice treated with combination of irinotecan and gefitinib survived significantly longer than those treated with irinotecan alone or gefitinib alone. In conclusion, gefitinib is shown to interact with BCRP. BCRP expression in a certain sort of cells is supposed to be one of the determinants of gefitinib sensitivity. Gefitinib inhibits the transporter function of BCRP and reverses BCRP-mediated drug resistance both in vitro and in vivo.