Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
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DOI：
10.1002/ijc.22643
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发表时间：
2007-07-01
影响因子：
6.4
通讯作者：
Myklebost, Ola
中科院分区：
文献类型：
--
作者：
Muller, Christoph R.;Paulsen, Erik B.;Myklebost, Ola
MDM 2拮抗剂Nutlin 3A可有效诱导MDM 2扩增的骨肉瘤细胞系凋亡。然而，基于Nutlin的治疗可能在更常见的肉瘤类型中更重要，因为这种畸变是常见的。分化良好和去分化的脂肪肉瘤具有复杂的标记染色体，始终包括MDM 2基因座的多个拷贝。由于扩增似乎是这些肿瘤中的主要畸变，而骨肉瘤中的扩增通常是进展标志物，因此潜在的生物学机制可能不同。因此，我们研究了在几个脂肪肉瘤细胞系与这些标志物，以及其他肉瘤细胞系的面板Nutlin治疗的分子反应。我们报道Nutlin在体外有效稳定了具有扩增的MDM 2的脂肪肉瘤细胞中的p53并诱导下游p53依赖性转录和凋亡。在没有扩增的MDM 2但具有wt TP 53的细胞系上也观察到Nutlin的一些作用，但没有诱导凋亡。据报道，MDM 4蛋白干扰p53的再激活，但在MDM 2扩增的细胞中检测不到。因此，Nutlin代表了一种有前途的新的治疗原则，用于治疗越来越多的肉瘤。(C)2007 Wiley-Liss，Inc.
The MDM2-antagonist Nutlin 3A can efficiently induce apoptosis in osteosarcoma cell lines with amplified MDM2. However, Nutlin-based therapy could be even more important in more common sarcoma types where this aberration is frequent. The well- and dedifferentiated liposarcomas have complex marker chromosomes, consistently including multiple copies of the MDM2 locus. Since amplification seems to be a primary aberration in these tumors, whereas amplification in osteosarcoma generally is a progression marker, the underlying biological mechanisms may be different. We have therefore investigated the molecular response to Nutlin treatment in several liposarcoma cell lines with such markers, as well as a panel of other sarcoma cell lines. We report that Nutlin efficiently stabilized p53 and induced downstream p53 dependent transcription and apoptosis in liposarcoma cells with amplified MDM2 in vitro. Some effect of Nutlin was also observed on cell lines without amplified MDM2 but with wt TP53, but no apoptosis was induced. The MDM4 protein, reported to interfere with the reactivation of p53, was undetectable in cells with amplified MDM2. Thus, Nutlin represents a promising new therapeutic principle for the treatment of an increasing group of sarcomas. (C) 2007 Wiley-Liss, Inc.