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

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

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.

Affiliation

Department of Clinical Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Journal Details

This article was published in the following journal.

Name: Cancer letters
ISSN: 1872-7980
Pages: 161-70

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