新型糖原合成激酶-3β抑制剂——多吡啶钌配合物的抗肿瘤研究

Research in anti-tumor activity of the novel GSK-3β inhibitor-polypyridyl ruthenium complexes

目的探讨多吡啶钌配合物∧-[Ru(bpy)2(pyip)]2+作为GSK-3β抑制剂在体外诱导人脑胶质瘤SWO-38细胞凋亡的机制。方法 MTT法从手性拆分的8种钌配合物中筛选出高活性、低毒性的配合物∧-[Ru(bpy)2(pyip)]2+,观察不同浓度该配合物作用下SWO-38细胞的增殖情况;应用AnnexinⅤ-FITC/PI双染流式细胞术检测不同浓度该配合物对SWO-38细胞凋亡的影响,Western blot法检测p-GSK-3βSer9蛋白的表达水平。结果 MTT法显示配合物可明显抑制SWO-38细胞的增殖,处理浓度大于10μmol·L-1组与对照组相比差异有显著性(P<0.05);流式细胞术显示配合物可明显诱导SWO-38细胞凋亡(P<0.05),处理浓度10、30、50μmol·L-1组的p-GSK-3βSer9蛋白表达水平高于对照组(P<0.05)。结论钌配合物∧-[Ru(bpy)2(pyip)]2+的抗肿瘤机制可能与GSK-3β的活性被抑制有关,该活性的抑制可诱导SWO-38细胞凋亡,且该作用呈剂量依赖性。

Aim To investigate the mechanism of apoptosis on human glioma SWO-38 cells induced by polypyridyl ruthenium complex∧-[Ru（bpy） 2（pyip） ]2＋as the inhibitor of GSK-3βin vitro.MethodsThe right complex∧-[Ru（bpy） 2（pyip） ]2＋with highest activity and lowest toxicity from eight kinds of polypyridyl ruthenium complexes with chiral separation were filtered by MTT colorimetric assay,and the proliferation of the cells with different concentrations of the complex was detected;FITC-AnnexinⅤ/PI double labelling was used to detect the apoptosis of SWO-38 cells;Western blot was employed to analyze the expression of p-GSK-3β Ser9 protein.Results MTT showed the complex could inhibit the growth of SWO-38 cells obviously;compared the dosing concentrations10 μmol·L -1 and that of the control group,the proliferation rates of SWO-38 cells had some differences（P 0.05） ;Flow cytometry showed the complex could significantly induce the apoptosis of SWO-38 cells;Western blot showed that compared with the control group,the level of p-GSK-3β Ser9 was up-regulated after treatment with 10,30,50μmol·L-1 concentrations of the complex（P0.05） .Conclusions The anti-tumor mechanism of the ruthenium complex∧-[Ru（bpy） 2（pyip） ]2＋may correlate with the inhibition of the activity of GSK-3βprotein which results in the apoptosis of SWO-38 cells,and these effects were dose dependent.