Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States.
Eur J Cancer. 2010 Apr;46(6):1122-31. doi: 10.1016/j.ejca.2010.01.015. Epub 2010 Feb 13.
Small molecule inhibitors (SMIs) of murine double minute 2 (MDM2) are known to restore the apoptotic and cell cycle regulatory functions of p53 by disrupting the MDM2-p53 interaction. In principle, these SMIs are not effective against tumours with mutation in the tumour suppressor p53 (mut-p53), which is known to be present in approximately 50% of all cancers. In this study we are reporting, for the first time, that MI-319 in combination with cisplatin induced cell growth inhibition and apoptosis in pancreatic cancer (PC) cells irrespective of their p53 mutational status. MI-319-cisplatin combination synergistically suppressed cell growth (MTT Combination Index [CI]<1) and colony formation (clonogenic assay) and induced apoptosis. Western blot analysis and siRNA silencing studies in mutant as well as p53 null cells highlighted a mechanism involving p73 which is also known to be under the regulation of MDM2, and unlike p53, it is rarely mutated in PC. Down-regulating MDM2 using siRNA enhanced p73 reactivation and increased cell death. Further, the combination effectively reduced tumour growth in both wt-p53 and mut-p53 tumour xenograft models (50% Capan-2 animals were tumour free). Consistent with our in vitro results, remnant tumour tissue analysis showed up-regulation of p73 and the cell cycle regulator p21. In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53.
小分子抑制剂（SMIs）的鼠双微体 2（MDM2）已知通过破坏 MDM2-p53 相互作用来恢复 p53 的凋亡和细胞周期调节功能。原则上，这些 SMIs 对肿瘤抑制基因 p53 （mut-p53）突变的肿瘤无效，大约 50%的所有癌症中都存在这种突变。在这项研究中，我们首次报道，MI-319 联合顺铂可诱导胰腺癌（PC）细胞的生长抑制和凋亡，而与 p53 突变状态无关。MI-319-顺铂联合协同抑制细胞生长（MTT 联合指数 [CI] <1）和集落形成（集落形成测定）并诱导凋亡。在突变和 p53 缺失细胞中的 Western blot 分析和 siRNA 沉默研究强调了一种涉及 p73 的机制，p73 也受 MDM2 调控，与 p53 不同，它在 PC 中很少发生突变。使用 siRNA 下调 MDM2 增强了 p73 的再激活并增加了细胞死亡。此外，该联合疗法有效地减少了 wt-p53 和 mut-p53 肿瘤异种移植模型中的肿瘤生长（50%的 Capan-2 动物无肿瘤）。与我们的体外结果一致，残留肿瘤组织分析显示 p73 和细胞周期调节剂 p21 的上调。总之，这项研究强调了 MDM2 抑制剂与顺铂联合应用的新作用，因此值得在含有 wt-p53 和 mut-p53 的人类胰腺肿瘤中进行进一步的临床研究。
