Distinct effects of dinuclear ruthenium(III) complexes on cell proliferation and on cell cycle regulation in human and murine tumor cell lines
Distinct effects of dinuclear ruthenium(III) complexes on cell proliferation and on cell cycle regulation in human and murine tumor cell lines
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DOI：
10.1124/jpet.102.047803
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发表时间：
2003-05-01
影响因子：
3.5
通讯作者：
Sava, G
中科院分区：
文献类型：
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作者：
Bergamo, A;Stocco, G;Sava, G
我们研究了一系列双核钌配合物的生物学活性和抗肿瘤活性。本研究的目的是比较这些新化合物在体外对细胞增殖、细胞在细胞周期阶段的分布以及参与细胞周期调节的一些蛋白质表达的影响。结果显示，该化合物对人类和小鼠细胞系有轻微的细胞毒活性，这种活性在长期暴露于细胞刺激后更为明显。八种双核配合物中的两种[即化合物D3 (Na-2[{RuCl4(dmso-S)}（2)(mu-bipy)]）和D7 ([NH4][{RuCl4(dmso-S)}(mu-pyz){RuCl3（dmso-S)(dmso-O)}]）对细胞周期分布的影响类似于咪唑反式咪唑二甲基亚砜四氯膦酸盐（NAMI-A），而其他化合物对该参数的影响很小或可以忽略。如果我们将细胞周期修饰的诱导与肿瘤细胞对钌的摄取以及调节细胞周期的蛋白的调节联系起来，我们可能会强调G(2)-M细胞周期阻滞的诱导与细胞内钌的阈值浓度的实现有关，这取决于所使用的细胞系，并且在免疫印迹法检测的细胞周期调节蛋白中，只有周期蛋白B似乎被显著修饰。这项体外研究表明，双核钌配合物可能具有与单体NAMI-A相似的行为。这些结果鼓励他们在体内模型的药理学性质的未来实验。
We have examined the biological and antitumor activity of a series of dinuclear ruthenium complexes. The aim of this study was to compare the in vitro effects of these new compounds on cell proliferation, cell distribution among cell cycle phases, and the expression of some proteins involved in cell cycle regulation. Results obtained show a mild cytotoxic activity against human and murine cell lines, more evident after prolonged exposure of cell challenge. Two of the eight dinuclear complexes [ namely, compounds D3 (Na-2[{RuCl4(dmso-S)}(2)(mu-bipy)]) and D7 ([NH4][{RuCl4(dmso-S)}(mu-pyz){RuCl3(dmso-S)(dmso-O)}]) modify cell cycle distribution similarly to imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A), whereas the others have a low or negligible effect on this parameter. If we correlate the induction of cell cycle modifications with ruthenium uptake by tumor cells and with the modulation of proteins regulating cell cycle, we may stress that the induction of G(2)-M cell cycle arrest is related to the achievement of a threshold concentration of ruthenium inside the cells, which is dependent on the cell line being used, and that only cyclin B, among cell cycle regulating proteins examined by immunoblotting assays, appears to be significantly modified. This in vitro study shows that dinuclear ruthenium complexes may have a behavior similar to that of the monomer NAMI-A. These results encourage the future experimentation of their pharmacological properties in in vivo models.