P-glycoprotein inhibition by glibenclamide and related compounds
P-glycoprotein inhibition by glibenclamide and related compounds
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DOI：
10.1007/s004240050829
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发表时间：
1999-04-01
影响因子：
4.5
通讯作者：
Beauwens, R
中科院分区：
文献类型：
--
作者：
Golstein, PE;Boom, A;Beauwens, R
众所周知，格列本脲可与磺脲类受体（SUR）相互作用，并且最近显示可抑制囊性纤维化跨膜传导调节蛋白（CFTR），这两种蛋白均为ABC [腺苷5 '-三磷酸（ATP）结合盒]转运蛋白的成员。研究了格列本脲和两种合成磺酰氰基胍衍生物（称为BM-208和BM-223）对P-糖蛋白（负责癌细胞多药耐药（MDR）的主要ABC转运蛋白）的影响。为此，我们采用了表达或不表达P-糖蛋白的不同细胞系，如通过蛋白质印迹法所证实的：首先，选自源自急性白血病的人T细胞系（CEM）的肿瘤细胞系（VBL 600）：第二，来自大鼠结肠腺癌的上皮细胞系（CC 531（mdr+））和最后，来源于负鼠肾近端小管的非肿瘤上皮细胞系（OK）。格列本脲和两种相关衍生物抑制P-糖蛋白，因为首先，它们仅在P-糖蛋白表达细胞系中急剧增加[H-3]秋水仙碱蓄积;其次，BM-223逆转MDR现象，与维拉帕米非常相似。BM-208和BM-223可阻断[H-3]azidopine对P-糖蛋白的光亲和标记。此外，格列本脲本身是P-糖蛋白的底物，因为[H-3]格列本脲的细胞蓄积较低，并且通过加入P-糖蛋白底物（例如，长春碱和环孢菌素）。我们得出结论，格列本脲和两个磺酰氰基胍衍生物抑制P-糖蛋白和磺脲类药物似乎是ABC转运蛋白的一般抑制剂，这表明与一些保守的基序的相互作用。
Glibenclamide is well known to interact with the sulphonylurea receptor (SUR) and has been shown more recently to inhibit the cystic fibrosis transmembrane conductance regulator protein (CFTR), both proteins that are members of the ABC [adenosine 5'-triphosphate (ATP)-binding cassette] transporters. The effect of glibenclamide and two synthetic sulphonylcyanoguanidine derivatives (dubbed BM-208 and BM-223) was examined on P-glycoprotein, the major ABC transporter responsible for multidrug resistance (MDR) in cancer cells. To this end, we employed different cell lines that do or do not express P-glycoprotein, as confirmed by Western blotting: first, a tumour cell line (VBL600) selected from a human T-cell line (CEM) derived from an acute leukaemia: second, an epithelial cell line derived from a rat colonic adenocarcinoma (CC531(mdr+)) and finally, a non tumour epithelial cell line derived from the proximal tubule of the opossum kidney (OK). Glibenclamide and the two related derivatives inhibited P-glycoprotein because firstly, they acutely increased [H-3]colchicine accumulation in P-glycoprotein-expressing cell lines only; secondly BM-223 reversed the MDR phenomenon, quite similarly to verapamil. by enhancing the cytotoxicity of colchicine, taxol and vinblastine and thirdly, BM-208 and BM-223 blocked the photoaffinity-labelling of P-glycoprotein by [H-3]azidopine. Further morel glibenclamide is itself a substrate for P-glycoprotein, since the cellular accumulation of [H-3]glibenclamide was low and substantially increased by addition of P-glycoprotein substrates (e.g., vinblastine and cyclosporine) only in the P-glycoprotein-expressing cell lines. We conclude that glibenclamide and two sulphonylcyanoguanidine derivatives inhibit P-glycoprotein and that sulphonylurea drugs would appear to be general inhibitors of ABC transporters, suggesting an interaction with some conserved motif.