Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
Neurosci Lett. 2012 Mar 28;513(1):106-10. doi: 10.1016/j.neulet.2012.02.022. Epub 2012 Feb 17.
A critical component of the cellular stress response, the p53 tumor suppressor protein must be functional for many cancer therapies to be effective. Adjuvant therapies that augment p53 function are predicted to sensitize tumor cells to cancer therapies that rely upon p53 for their efficacy. Of those strategies currently being explored to enhance p53 function, inhibition of the ubiquitin ligase, MDM2, a negative regulator of p53, has shown promise. Here, we investigated whether MDM2 antagonism might be effective in inducing cell death in human medulloblastoma (MB) cells. Nutlin-3, a small-molecule inhibitor of MDM2, potently induced apoptosis in MB cells with wild-type TP53. Moreover, nutlin-3 potentiated p53 activation and growth impairment of MB cells in combination with the classic DNA-damaging agent doxorubicin. Together, these results support the concept that MDM2 antagonists may be therapeutically beneficial for patients with MB tumors.
细胞应激反应的一个关键组成部分是 p53 肿瘤抑制蛋白，许多癌症疗法要想有效，就必须发挥功能。预测增强 p53 功能的辅助疗法将使肿瘤细胞对依赖 p53 发挥疗效的癌症疗法更加敏感。在目前正在探索的增强 p53 功能的策略中，抑制泛素连接酶 MDM2（p53 的负调控因子）显示出了一定的前景。在这里，我们研究了 MDM2 拮抗作用是否可能有效地诱导人髓母细胞瘤（MB）细胞死亡。MDM2 的小分子抑制剂 Nutlin-3 可强烈诱导野生型 TP53 的 MB 细胞发生凋亡。此外，Nutlin-3 与经典的 DNA 损伤药物阿霉素联合使用，可增强 p53 的激活和 MB 细胞的生长抑制。总之，这些结果支持这样一种观点，即 MDM2 拮抗剂可能对患有 MB 肿瘤的患者具有治疗益处。
