Tovar Christian, Rosinski James, Filipovic Zoran, Higgins Brian, Kolinsky Kenneth, Hilton Holly, Zhao Xiaolan, Vu Binh T, Qing Weiguo, Packman Kathryn, Myklebost Ola, Heimbrook David C, Vassilev Lyubomir T
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1888-93. doi: 10.1073/pnas.0507493103. Epub 2006 Jan 27.
The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction.
在所有人类肿瘤中，有一半的肿瘤其p53肿瘤抑制蛋白保持野生型构象和转录活性，激活p53可能带来治疗益处。然而，p53途径中存在的信号缺陷可能会损害p53功能。使用小分子MDM2拮抗剂nutlin-3来探究p53下游信号，我们发现，在多个表达野生型p53的肿瘤衍生细胞系中，p53途径的细胞周期阻滞功能得以保留，但许多细胞系经历p53依赖性凋亡的能力有所下降。基因阵列分析显示多个凋亡相关基因的表达减弱。在体外和体内，mdm2基因扩增的癌细胞对nutlin-3最为敏感，这表明MDM2过表达可能是这些细胞p53途径中唯一的异常情况。Nutlin-3对MDM2表达正常的肿瘤也显示出良好疗效，这表明许多野生型p53肿瘤患者可能会从p53-MDM2相互作用拮抗剂中获益。
