Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction
Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction
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DOI：
10.1016/j.lfs.2015.10.015
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发表时间：
2015-12-01
期刊：
影响因子：
6.1
通讯作者：
Saraiva, Lucilia
中科院分区：
文献类型：
--
作者：
Leao, Mariana;Soares, Joana;Saraiva, Lucilia
Aim: Chalcones are naturally occurring compounds with recognized anticancer activity. It was recently shown that the O-prenyl derivative (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) had a remarkably increased cytotoxicity against human tumour cells compared to its precursor. With this study, we aimed to investigate the molecular mechanism underlying the improved tumour cytotoxicity of prenylchalcone 2.Main methods: The impact of chalcones 1 and 2 on p53-MDM2 interaction was investigated using yeast growth-inhibitory and p53 transactivation assays. Their tumour growth-inhibitory effects were assessed on human colon adenocarcinoma HCT116 cell lines with wild-type p53 and its p53-null derivative, followed by analysis of cell cycle and apoptosis. In tumour cells, the activation of a mitochondrial pathway was checked by analysis of reactive oxygen species generation, Sax mitochondrial translocation and cytochrome c release. Additionally, the upregulation of p53 transcriptional activity was investigated through Western blot analysis of p53 target expression levels, and the disruption of the p53--MDM2 interaction was confirmed by co-immunoprecipitation.Key findings: The potent cell tumour growth-inhibitory activity of prenylchalcone 2 was associated with the activation of a p53 pathway involving cell cycle arrest and a mitochondria-dependent apoptosis. Furthermore, a correlation between the distinct cytotoxicity of chalcones 1 and 2 and their ability to disrupt the p53-MDM2 interaction was established.Significance: This work shows that prenylation is a determinant factor for the enhancement of chalcones tumour cytotoxicity by improving their ability to disrupt the p53-MDM2 interaction. Prenylchalcone 2 represents a starting basis for the design of new p53-MDM2 interaction inhibitors with improved antitumor properties. (C) 2015 Elsevier Inc. All rights reserved.
