Screening novel, potent multidrug-resistant modulators from imidazole derivatives
Screening novel, potent multidrug-resistant modulators from imidazole derivatives
复制标题
从咪唑衍生物中筛选新型、有效的多重耐药调节剂。
DOI：
10.3727/0965040041292378
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发表时间：
2004-01-01
影响因子：
3.1
通讯作者：
Fu, LW
中科院分区：
文献类型：
--
作者：
Chen, LM;Wu, XP;Fu, LW
肿瘤细胞过度表达 P-糖蛋白 (P-gp) 会导致对结构上不相关的抗癌药物产生多药耐药性 (MDR)。多药耐药相关细胞毒素和多药耐药调节剂的联合治疗是克服临床多药耐药的一种有前景的策略。本研究旨在从咪唑衍生物中筛选有效的 MDR 调节剂。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑 (MTT) 测定法测定细胞毒性。通过荧光分光光度法检测细胞内阿霉素（Dox）的积累。通过流式细胞术（FCM）检测罗丹明123积累来检查P-gp的功能。在咪唑衍生物中，FG020326、FG020327 和 FG020318 的逆转 MDR 活性比众所周知的正 MDR 调节剂维拉帕米强三到四倍。咪唑衍生物显着增加MDR细胞中Dox的积累并抑制P-gp功能，这通过增加罗丹明的积累来表现。 MDR倍数逆转与罗丹明累积量的增加有关。 FG020326、FG020327 和 FG020318 在体外表现出有效的 MDR 逆转活性。它们逆转MDR的机制与抑制P-gp功能和增加抗癌积累有关。这些结果表明 FG020326、FG020327 和 FG020318 有希望进一步研究和开发。
The overexpression of P-glycoprotein (P-gp) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Combined therapy with MDR-related cytotoxins and MDR modulators is a promising strategy to overcome clinical MDR. This study was designed to screen potent MDR modulators from imidazole derivatives. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The intracellular accumulation of doxorubicin (Dox) was detected by fluorescence spectrophotometry. The function of P-gp was examined by Rhodamine 123 accumulation detected with flow cytometry (FCM). Among imidazole derivatives, FG020326, FG020327, and FG020318 were found to possess three- to fourfold stronger reversal MDR activity than verapamil, a well-known positive MDR modulator. Imidazole derivatives significantly increased the Dox accumulation and inhibited P-gp function exhibited by the increase of Rhodamine accumulation in MDR cells. The fold reversal of MDR was relative with the increase of Rhodamine accumulation. FG020326, FG020327, and FG020318 showed potent MDR reversal activity in vitro. Their mechanism of MDR reversal is associated with the inhibition of P-gp function and the increase of anticancer accumulation. These results suggest FG020326, FG020327, and FG020318 are promising to further study and develop.