西地那非和伐地那非逆转MRP7介导的紫杉醇耐药

目的对5型磷酸二酯酶抑制剂能否逆转MRP7介导的化疗药物耐药作用进行研究。方法细胞毒性测定用MTT法;细胞内药物积累实验用液闪仪检测放射性标记物;蛋白表达用Western blotting检测。结果 5μmol/L的西地那非、伐地那非和他达拉非使HEK-MRP7细胞对紫杉醇敏感性分别增加9.8、10.7和1.8倍。在药物积累实验中,西地那非、伐地那非和他达拉非能明显地增加HEK-MRP7细胞中的3H]-紫杉醇的积累,在5μmol/L时,3H]-紫杉醇的积累水平分别增加了3.0、3.3和1.8倍。西地那非和伐地那非能逆转MRP7耐紫杉醇药物的效果明显优于他达拉非。Western blot结果显示西地那非和伐地那非作用后对MRP7蛋白的表达没有影响。结论西地那非和伐地那非通过抑制耐药蛋白MRP7的外排泵功能来有效增加HEK-MRP7细胞内的抗肿瘤药物紫杉醇的积累。

Sildenafil and vardenafil reverse MRP7-mediated drug resistance to paclitaxel

Objective Previously,we had shown that sildenafil and vardenafil could reverse P-gp-mediated multidrug resistance(MDR) in vitro.This study was designed to determine whether PDE5 inhibitors have the potential to reverse MRP7-mediated chemotherapeutic drug resistance.Methods The MTT assay was used to access cytotoxicity.The intracellular accumulation of -paclitaxel was measured in liquid scintillation analyzer.Western blotting was used to determine the MRP7 protein expression.Results Sildenafil,vardenafil and tadalafil at 5 μmol/L significantly increased the sensitivity of HEK-MRP7 cells to paclitaxel by 9.8-,10.7-and 1.8-fold,respectively.Consistent with the cytotoxicity results,the drug accumulation data indicated sildenafil,vardenafil and tadalafil at 5 μmol/L significantly enhanced the intracellular accumulation of -paclitaxel in HEK-MRP7 cells by 3.0-,3.3-and 1.8-fold,respectively.The reversal efficacy of tadalafil was weaker than that of sildenafil and vardenafil.Western blot analysis indicated that sildenafil and vardenafil did not alter the expression of MRP7.Conclusion Sildenafil and vardenafil significantly enhanced the cytotoxicity of paclitaxel to HEK-MRP7 cells through inhibition of the drug efflux function of MRP7 rather than alteration of the expression of MRP7.