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

被引：35
|
作者：
Jin, Linhua [1 ]
Tabe, Yoko [1 ]
Kojima, Kensuke [2 ]
Zhou, Yixin [1 ]
Pittaluga, Stefania [4 ]
Konopleva, Marina [3 ]
Miida, Takashi [1 ]
Raffeld, Mark [4 ]
机构：
[1] Juntendo Univ, Sch Med, Dept Clin Pathol, Tokyo 113, Japan
[2] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[4] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA
来源：
CANCER LETTERS | 2010年 / 299卷 / 02期
基金：
日本科学技术振兴机构;
关键词：
Mantle cell lymphoma; TP53; MDM2; Bortezomib; Nutlin-3; PROTEASOME INHIBITOR BORTEZOMIB; PHASE-II; DNA-DAMAGE; P53; ACTIVATION; NOXA; LINE; ESTABLISHMENT; SENSITIVITY; EXPRESSION;
D O I：
10.1016/j.canlet.2010.08.015
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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 (c) 2010 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码：161 / 170
页数：10
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