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

Eur J Cancer. 2010 Apr;46(6):1122-31. doi: 10.1016/j.ejca.2010.01.015. Epub 2010 Feb 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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