MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function.
MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function.
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DOI：
10.1016/j.ejca.2010.01.015
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发表时间：
2010-04
影响因子：
8.4
通讯作者：
Mohammad, Ramzi M.
中科院分区：
文献类型：
--
作者：
Azmi, Asfar S.;Aboukameel, Amro;Banerjee, Sanjeev;Wang, Zhiwei;Mohammad, Momin;Wu, Jack;Wang, Shaomeng;Yang, Dajun;Philip, Philip A.;Sarkar, Fazlul H.;Mohammad, Ramzi M.
已知MDM 2的小分子抑制剂（SMI）通过破坏MDM 2-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SMI对具有mut-p53的肿瘤无效，已知mut-p53存在于约50%的所有癌症中。在这项研究中，我们首次报告，MI-319与顺铂联合诱导胰腺癌（PC）细胞的细胞生长抑制和凋亡，无论其p53突变状态如何。MI-319-顺铂组合协同抑制细胞生长（MTT CI<1）和集落形成（克隆形成测定）并诱导细胞凋亡。蛋白质印迹分析和siRNA沉默的研究，突变体以及p53无效的细胞强调了一个机制，涉及p73，这也是已知的MDM 2的调控下，不像p53，它很少在PC中突变。使用siRNA下调MDM 2增强了p73再活化并增加了细胞死亡。此外，该组合有效地减少了wt-p53和mut-p53肿瘤异种移植模型中的肿瘤生长（50% Capan-2动物无肿瘤）。与我们的体外结果一致，残余肿瘤组织分析显示p73和细胞周期调节因子p21上调。总之，这项研究强调了MDM 2抑制剂与顺铂联合的新作用，因此需要在含有wt-p53和mut-p53的人胰腺肿瘤中进行进一步的临床研究。
Small molecule inhibitors (SMIs) of 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 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 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.
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