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

• Published in: Cancer letters Vol. 299; no. 2; pp. 161 - 170
• Main Authors: Jin, Linhua, Tabe, Yoko, Kojima, Kensuke, Zhou, Yixin, Pittaluga, Stefania, Konopleva, Marina, Miida, Takashi, Raffeld, Mark
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 28.12.2010; Elsevier Limited
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-2-Associated X Protein - metabolism; Blotting, Western; Boronic Acids - pharmacology; Bortezomib; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Synergism; Hematology, Oncology and Palliative Medicine; Humans; Imidazoles - pharmacology; Lymphoma, Mantle-Cell - genetics; Lymphoma, Mantle-Cell - metabolism; Lymphoma, Mantle-Cell - pathology; Mantle cell lymphoma; MDM2; Medical research; Mitochondria - drug effects; Mitochondria - metabolism; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Nutlin-3; 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; TP53; Tumor Suppressor Protein p53 - genetics; Nutlin-3; MDM2; Bortezomib; TP53; Mantle cell lymphoma
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2010.08.015

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.