MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function.

Abstract

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.

• Authors: Asfar S Azmi, Amro Aboukameel, Sanjeev Banerjee, Zhiwei Wang, Momin Mohammad, Jack Wu, Shaomeng Wang, Dajun Yang, Philip A Philip, Fazlul H Sarkar, Ramzi M Mohammad
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 46 Issue 6 Pg. 1122-31 (Apr 2010) ISSN: 1879-0852 [Electronic] England
• PMID: 20156675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• DNA-Binding Proteins
• Indoles
• MI 319
• Nuclear Proteins
• RNA, Small Interfering
• Spiro Compounds
• TP73 protein, human
• Trp73 protein, mouse
• Tumor Protein p73
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Cisplatin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, genetics)
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunohistochemistry
• Indoles (pharmacology)
• Mice
• Nuclear Proteins (antagonists & inhibitors, genetics)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, genetics, physiology)
• RNA, Small Interfering (pharmacology)
• Spiro Compounds (pharmacology)
• Tumor Protein p73
• Tumor Suppressor Protein p53 (genetics, physiology)
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics)