A small molecule that disrupts Mdm2-p53 binding activates p53, induces apoptosis and sensitizes lung cancer cells to chemotherapy
A small molecule that disrupts Mdm2-p53 binding activates p53, induces apoptosis and sensitizes lung cancer cells to chemotherapy
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DOI：
10.4161/cbt.7.6.5841
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Sun, Yi
中科院分区：
文献类型：
--
作者：
Sun, Steven H.;Zheng, Min;Sun, Yi
MDM2与P53结合并促进其降解。最近发现了一类小分子MDM2抑制剂(MI)，它能与MDM2结合并破坏MDM2与P53的结合。MI-43对两对不同p53状态的人肺癌细胞株：腺癌A549(p53野生型，wt)和H522(p53缺失)和非小细胞肺癌H460(P53wt)和H1299(p53缺失)进行了药效试验。MI-43只诱导p53及其下游靶基因MDM2、p21、NOXA和PUMA在wt p53细胞中积聚，表明MDM2-P53结合的破坏增加了转录活性的P53。MI-43以P53依赖的方式优先抑制含P53的wt细胞的生长，但对P53阴性细胞的抑制作用较弱。机制上，MI-43在低浓度时通过p21诱导G(1)或G(2)期停滞，在高浓度时通过PUMA/NOXA诱导细胞凋亡。重要的是，MI-43对正常胎儿肺成纤维细胞MRC5细胞的毒性要小得多。最后，当MI-43联合使用时，MI-43使耐药的A549细胞对依托泊苷诱导的细胞凋亡敏感。因此，MI-43或其类似物可进一步开发为一类新型的肺癌细胞抗癌药物，可单独或与化疗药物联合使用。
Mdm2 binds to p53 and promotes its degradation. A class of small molecule Mdm2 inhibitors ( MI) was recently discovered that binds to Mdm2 and disrupts Mdm2-p53 binding. The efficacy of MI-43 was tested against two pairs of human lung cancer lines differing in p53 status: adenocarcinoma A549 (p53 wild-type, wt) and H522 (p53-null) and non-small cell lung carcinoma H460 (p53wt) and H1299 (p53-null). MI-43 induced the accumulation of p53 and its downstream target genes, Mdm2, p21, Noxa and Puma only in wt p53-containing cells, indicating that disruption of Mdm2-p53 binding increases p53, which is transcriptionally active. MI-43 preferentially inhibited the growth of wt p53-containing cells in a p53 dependent manner, but was much less effective in p53-null cells. Mechanistically, MI-43 induced G(1) or G(2) arrest at low concentration as result of p21 induction, and apoptosis at high concentration due to Puma/Noxa induction. Importantly, MI-43 is much less toxic to normal fetal lung fibroblast, MRC5 cells. Finally, when used in combination, MI-43 sensitized chemo-resistant A549 cells to etoposide-induced apoptosis. Thus, MI-43 or its analogues could be further developed as a novel class of anticancer drug for lung cancer cells harboring wt p53 as a single agent or in combination with chemo-drugs.