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, Bax mitochondrial translocation and cytochrome c release. Additionally, the up-regulation 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.