MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma

Cancer Lett. 2010 Dec 28;299(2):161-70. doi: 10.1016/j.canlet.2010.08.015. Epub 2010 Sep 17.

Abstract

This study demonstrated a pronounced synergistic growth-inhibitory effect of an MDM2 inhibitor Nutlin-3 and a proteasome inhibitor bortezomib in mantle cell lymphoma (MCL) cells regardless of TP53 mutant status and innate bortezomib sensitivity. In the mutant TP53 MCL cells which are intrinsically resistant to bortezomib, the combination of Nutlin-3/bortezomib synergistically induced cytotoxicity through the mitochondrial apoptotic pathway mediated by transcription-independent upregulation of NOXA, sequestration of MCL-1, activation of BAX, BAK, caspase-9 and -3. In the bortezomib sensitive wild-type TP53 MCL cells, the Nutlin-3/bortezomib combination caused G0/G1 cell cycle arrest followed by the increase in apoptosis induction. These findings indicate potential therapeutic efficacy of Nutlin-3/bortezomib combination for the treatment of chemorefractory MCL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Blotting, Western
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Humans
  • Imidazoles / pharmacology*
  • Lymphoma, Mantle-Cell / genetics
  • Lymphoma, Mantle-Cell / metabolism
  • Lymphoma, Mantle-Cell / pathology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mutation
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrazines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Protein p53 / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Imidazoles
  • Myeloid Cell Leukemia Sequence 1 Protein
  • PMAIP1 protein, human
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazines
  • Tumor Suppressor Protein p53
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • nutlin 3
  • Bortezomib
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Caspase 3
  • Caspase 9