TY - JOUR
T1 - Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction
AU - Leão, Mariana
AU - Soares, Joana
AU - Gomes, Sara
AU - Raimundo, Liliana
AU - Ramos, Helena
AU - Bessa, Cláudia
AU - Queiroz, Glória
AU - Domingos, Sofia
AU - Pinto, Madalena
AU - Inga, Alberto
AU - Cidade, Honorina
AU - Saraiva, Lucília
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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, 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.
AB - 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, 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.
KW - Anticancer
KW - Chalcones
KW - p53-MDM2 interaction
KW - Prenylation
KW - Tumour cytotoxicity
UR - http://www.scopus.com/inward/record.url?scp=84944769312&partnerID=8YFLogxK
U2 - 10.1016/j.lfs.2015.10.015
DO - 10.1016/j.lfs.2015.10.015
M3 - Article
C2 - 26475964
AN - SCOPUS:84944769312
VL - 142
SP - 60
EP - 65
JO - Life Sciences
JF - Life Sciences
SN - 0024-3205
ER -