Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia
Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2005-12-5148
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发表时间：
2006-08-01
期刊：
影响因子：
20.3
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
--
作者：
Kojima, Kensuke;Konopleva, Marina;Andreeff, Michael
虽然TP 53突变在B细胞慢性淋巴细胞白血病（CLL）中很少见，但Mdm 2过表达已被报道为p53功能障碍的另一种原因。我们研究了Mdm 2的小分子拮抗剂Nutlin-3a激活非遗传毒性p53在CLL中的潜在治疗用途。Nutlin-3a在来自先前未治疗的CLL患者的33个样品中的30个（91%）中诱导了显著的细胞凋亡;所有耐药样品都具有TP 53突变。低水平的Atm（共济失调毛细血管扩张突变）或高水平的Mdm 2（小鼠双分钟2）没有阻止Nutlin-3a诱导细胞凋亡。Nutlin-3a通过转录依赖性和转录非依赖性途径诱导p53介导的细胞凋亡。转录非依赖性途径的主要激活诱导比转录依赖性途径更明显的细胞凋亡，这表明转录非依赖性途径的激活足以启动CLL中p53介导的细胞凋亡。Nutlin-3a和氟达拉滨的联合治疗协同增加p53水平，并诱导Bax的构象变化和野生型p53细胞中的凋亡，但在突变型p53细胞中没有。在具有低Atm的氟达拉滨抗性样品中维持协同凋亡效应。结果表明，通过靶向Mdm 2-p53相互作用的p53的非遗传毒性激活为CLL提供了一种新的治疗策略。
Although TP53 mutations are rare in B-cell chronic lymphocytic leukemia (CLL), Mdm2 overexpression has been reported as an alternative cause of p53 dysfunction. We investigated the potential therapeutic use of nongenotoxic p53 activation by a small-molecule antagonist of Mdm2, Nutlin-3a, in CLL. Nutlin-3a induced significant apoptosis in 30 (91%) of 33 samples from previously untreated patients with CLL; all resistant samples had TP53 mutations. Low levels of Atm (ataxia telangiectasia mutated) or high levels of Mdm2 (murine double minute 2) did not prevent Nutlin-3a from inducing apoptosis. Nutlin-3a used transcription-dependent and transcription-independent pathways to induce p53-mediated apoptosis. Predominant activation of the transcription-independent pathway induced more pronounced apoptosis than that of the transcription-dependent pathway, suggesting that activation of the transcription-independent pathway is sufficient to initiate p53-mediated apoptosis in CLL. Combination treatment of Nutlin-3a and fludarabine synergistically increased p53 levels, and induced conformational change of Bax and apoptosis in wild-type p53 cells but not in cells with mutant p53. The synergistic apoptotic effect was maintained in samples with low Atm that were fludarabine resistant. Results suggest that the nongenotoxic activation of p53 by targeting the Mdm2-p53 interaction provides a novel therapeutic strategy for CLL.