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ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein

文献类型:期刊论文

作者Mi, Y.; Lou, L.
刊名BRITISH JOURNAL OF CANCER
出版日期2007-10-02
卷号97期号:7页码:934-940
关键词ZD6474 P-glycoprotein multidrug resistance
ISSN号0007-0920
DOI10.1038/sj.bjc.6603985
文献子类Article
英文摘要P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. This study was designed to examine whether ZD6474 reverses P-gp-mediated MDR in cancer cells. Here, we show that clinically achievable levels of ZD6474 reverse P-gp-mediated MDR of the P-gp-overexpressing cell lines derived from breast cancer, MCF-7/adriamycin (ADR), and human oral epidermoid carcinoma, KBV200 to ADR, docetaxel, and vinorelbine. This ability to reverse the P-gp-mediated resistance is comparable to that of another frequently used reversal agent known as verapamil. ZD6474 itself moderately inhibits the proliferation of both MCF-7 and MCF-7/ADR cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that ZD6474 may not be a substrate of P-gp. In addition, ZD6474 increases the intracellular accumulation of the P-gp substrate, rhodamine-123, and ADR, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Further studies show that ZD6474 stimulates ATPase activity in a dose-dependent manner, which is required for the proper function of P-gp. In contrast, ZD6474 does not inhibit the expression level of P-gp. Our results suggest that ZD6474 is capable of reversing MDR in cancer cells by directly inhibiting the function of P-gp, a finding that may have clinical implications for ZD6474.
WOS关键词TYROSINE KINASE INHIBITORS ; CANCER-CELLS ; PROTEIN ; ABCG2 ; TRANSPORTERS ; GEFITINIB ; GROWTH
WOS研究方向Oncology
语种英语
WOS记录号WOS:000249882000015
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/273131]  
专题药理学第一研究室
通讯作者Lou, L.
作者单位Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
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GB/T 7714
Mi, Y.,Lou, L.. ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein[J]. BRITISH JOURNAL OF CANCER,2007,97(7):934-940.
APA Mi, Y.,&Lou, L..(2007).ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein.BRITISH JOURNAL OF CANCER,97(7),934-940.
MLA Mi, Y.,et al."ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein".BRITISH JOURNAL OF CANCER 97.7(2007):934-940.

入库方式: OAI收割

来源:上海药物研究所

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