Ribas Judit, Boix Jacint, Meijer Laurent
CNRS, Cell Cycle Group, Station Biologique, B.P. 74, 29682 Roscoff cedex, Bretagne, France.
Exp Cell Res. 2006 Jul 15;312(12):2394-400. doi: 10.1016/j.yexcr.2006.04.021.
In this study, we have analyzed the consequences, on several neuroblastoma cell lines, of combined treatments with (R)-roscovitine (CYC202, Seliciclib), a CDK inhibitory drug, and nutlin-3, a p53 activating drug. Both compounds were found to synergize, causing significant levels of apoptosis in cultured cells when combined at sublethal concentrations. In SH-SY5Y cells, Bcl-XL protein overexpression protected from apoptosis induced by either nutlin-3 alone or the (R)-roscovitine plus nutlin-3 association but failed to prevent apoptosis triggered by (R)-roscovitine alone. Moreover, Western blot studies showed that (R)-roscovitine increased nutlin-3-mediated p53 stabilization. Therefore, we conclude the contribution of (R)-roscovitine to the synergism is basically the sensitization of SH-SY5Y cells to the action of nutlin-3 on p53. The relevance of this pharmacological synergism with respect to the treatment of neuroblastoma is discussed.
在本研究中，我们分析了CDK抑制药物（R）-罗可维汀（CYC202，塞利西利布）与p53激活药物Nutlin-3联合处理对几种神经母细胞瘤细胞系的影响。发现这两种化合物具有协同作用，当以亚致死浓度联合使用时，可在培养细胞中引起显著水平的细胞凋亡。在SH-SY5Y细胞中，Bcl-XL蛋白的过表达可保护细胞免受单独使用Nutlin-3或（R）-罗可维汀加Nutlin-3联合诱导的细胞凋亡，但不能阻止单独使用（R）-罗可维汀引发的细胞凋亡。此外，蛋白质印迹研究表明，（R）-罗可维汀可增强Nutlin-3介导的p53稳定性。因此，我们得出结论，（R）-罗可维汀对协同作用的贡献主要是使SH-SY5Y细胞对Nutlin-3对p53的作用敏感。本文讨论了这种药理协同作用在神经母细胞瘤治疗方面的相关性。
