Reversal of P-gp mediated multidrug resistance in-vitro and in-vivo by FG020318
Reversal of P-gp mediated multidrug resistance in-vitro and in-vivo by FG020318
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DOI：
10.1211/0022357043879
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发表时间：
2004-08-01
影响因子：
3.3
通讯作者：
Fu, LW
中科院分区：
文献类型：
--
作者：
Chen, LM;Liang, YJ;Fu, LW
肿瘤过度表达 P-糖蛋白 (P-gp) 会导致对结构和功能不相关的化疗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。本研究旨在探索新型化合物 2-[4-(2-吡啶-2-基-乙烯基)苯基]-4,5-双-(4-N,N-二乙氨基苯基)-1(H)-咪唑 (FG020318) 的体外和体内 MDR 逆转活性。使用四唑 (MTT) 测定来评估 FG020318 在两种表达 P-gp 的肿瘤细胞系 KBv200 和 MCF-7/adr 中逆转耐药性的能力。通过荧光分光光度法测定 MCF-7/adr 细胞系中的细胞内多柔比星积累。FG020318 对 P-gp 功能的影响通过 KBv200 细胞中罗丹明 123 (Rh123) 的积累来证明。建立KBv200细胞异种移植模型来研究FG020318逆转MDR的体内作用。 FG020318 本身对表达 P-gp 的 KBv200 细胞和 MCF-7/adr 细胞及其亲代药物敏感 KB 细胞和 MCF-7 细胞没有细胞毒性。 FG020318 可以显着增加 MCF-7/adr 细胞和 KBv200 细胞中 MDR 细胞对抗肿瘤药物（包括阿霉素和长春新碱）的敏感性。其逆转MDR的作用比阳性对照维拉帕米强得多。 FG020318还以浓度依赖性方式增加MCF-7/adr细胞中阿霉素的细胞内积累，但不影响药物敏感的MCF-7细胞中阿霉素的积累。添加FG020318也增加了耐药KBv200细胞中Rh123的积累，但在药物敏感的KB细胞中Rh123的积累不受FG020318的影响。 FG020318 增强了长春新碱对 KBv200 异种移植物的抗肿瘤活性，是一种有效的体内调节剂。我们的结果表明，FG020318 不仅在体外而且在体内都是一种高效、有效的 MDR 调节剂。 FG020318逆转耐药可能与增加抗癌药物积累及其抑制MDR肿瘤细胞的P-gp功能有关。
Overexpression of P-glycoprotein (P-gp) by tumours results in multidrug resistance (MDR) to structurally and functionally unrelated chemotherapeutic drugs. Combined therapy with MDR-related cytotoxins and MDR modulators is a promising strategy to overcome clinical MDR. This study was performed to explore the MDR reversal activity of a novel compound 2-[4-(2-pyridin-2-yl-vinyl) phenyl]-4,5-bis-(4-N,N-diethylaminophenyl)-1(H)-imidazole (FG020318) in-vitro and in-vivo. Tetrazolium (MTT) assay was used to evaluate the ability of FG020318 to reverse drug resistance in two P-gp-expressing tumour cell lines, KBv200 and MCF-7/adr. Intracellular doxorubicin accumulation was determined by fluorescence spectrophotometry in MCF-7/adr cell line The effect of FG020318 on P-gp function was demonstrated by rhodamine 123 (Rh123) accumulation in KBv200 cells. KBv200 cell xenograft models were established to study the in-vivo effect of FG020318 on reversing MDR. FG020318 was not cytotoxic by itself against P-gp expressing KBv200 cells and MCF-7/adr cells and their parental drug-sensitive KB cells and MCF-7 cells. FG020318 could significantly increase the sensitivity of MDR cells to antitumour drugs including doxorubicin and vincristine in MCF-7/adr cells and KBv200 cells, respectively. It was much stronger than the positive control verapamil in reversal of MDR. FG020318 also increased the intracellular accumulation of doxorubicin in a concentration-dependent manner in MCF-7/adr cells, but did not affect the accumulation of doxorubicin in drug-sensitive MCF-7 cells. The Rh123 accumulation in resistant KBv200 cells was also increased by the addition of FG020318, but Rh123 accumulation was not affected by FG020318 in drug-sensitive KB cells. FG020318 potentiated the antitumour activity of vincristine to KBv200 xenografts and was an efficacious modulator in-vivo. Our results suggested that FG020318 was a highly potent, efficacious MDR modulator not only in-vitro but also in-vivo. The reversal of drug resistance by FG020318 was probably related to the increased anticancer drug accumulation and its inhibition of P-gp function of MDR tumour cells.