An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals.
An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals.
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DOI：
10.1186/1476-4598-8-115
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发表时间：
2009-12-03
期刊：
影响因子：
37.3
通讯作者：
Al-Katib AM
中科院分区：
文献类型：
--
作者：
Mohammad RM;Wu J;Azmi AS;Aboukameel A;Sosin A;Wu S;Yang D;Wang S;Al-Katib AM
MI-319是一种合成小分子，旨在靶向MDM 2-P53相互作用。在预期的作用机制方面，它与MDM 2拮抗剂MI-219和Nutlin-3密切相关。本研究旨在评价MI-319在WSU-FSCCL（一种B细胞滤泡性淋巴瘤细胞系）中的抗淋巴瘤活性。为了比较的目的，在生长抑制和基因表达谱分析实验中，针对FSCCL和三种其他B细胞血液肿瘤细胞系并排评估MI-319、MI-219和Nutlin-3。显示MI-319以略高于MI-219和Nutlin-3的亲和力结合MDM 2蛋白。然而，细胞生长抑制和基因表达谱分析实验表明，这三种化合物对本研究中测试的肿瘤细胞系具有非常相似的效力。在体外，MI-319对FSCCL和四种患者细胞表现出最强的抗增殖活性，这些细胞都具有野生型p53。Western blotting、细胞周期和凋亡分析实验的数据表明，FSCCL表现出强烈的细胞周期阻滞和显著的凋亡性细胞死亡;突变型p53的细胞在药物浓度高达10 μM时没有表现出显著的凋亡性细胞死亡，但表现出较弱的和差异性的细胞周期反应。在我们的FSCCL全身小鼠模型中，MI-319被动物良好耐受，显示出对血液、脑和骨髓中的FSCCL-淋巴瘤细胞的有效性，并且通过赋予治疗组> 28%（%ILS，14.4天）的中位存活天数增加而实现显著的治疗影响（p < 0.0001）。总体而言，MI-319可能具有与MI-219和Nutlin-3相同的抗淋巴瘤效力。它是体外和体内抗FSCCL的有效药物，并有望进一步开发用于治疗保留野生型p53的滤泡性淋巴瘤。
MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments. MI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. In vitro, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 μM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days. Overall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL in vitro and in vivo and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.
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