Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction
Copyright © 2015 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:142 |
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| Enthalten in: |
Life sciences - 142(2015) vom: 01. Dez., Seite 60-5 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Leão, Mariana [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.02.2016 Date Revised 26.11.2016 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.lfs.2015.10.015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction |
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| 500 | |a Date Revised 26.11.2016 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2015 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Anticancer | |
| 650 | 4 | |a Chalcones | |
| 650 | 4 | |a Prenylation | |
| 650 | 4 | |a Tumour cytotoxicity | |
| 650 | 4 | |a p53–MDM2 interaction | |
| 650 | 7 | |a Chalcones |2 NLM | |
| 650 | 7 | |a TP53 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a MDM2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-mdm2 |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
| 700 | 1 | |a Soares, Joana |e verfasserin |4 aut | |
| 700 | 1 | |a Gomes, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Raimundo, Liliana |e verfasserin |4 aut | |
| 700 | 1 | |a Ramos, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Bessa, Cláudia |e verfasserin |4 aut | |
| 700 | 1 | |a Queiroz, Glória |e verfasserin |4 aut | |
| 700 | 1 | |a Domingos, Sofia |e verfasserin |4 aut | |
| 700 | 1 | |a Pinto, Madalena |e verfasserin |4 aut | |
| 700 | 1 | |a Inga, Alberto |e verfasserin |4 aut | |
| 700 | 1 | |a Cidade, Honorina |e verfasserin |4 aut | |
| 700 | 1 | |a Saraiva, Lucília |e verfasserin |4 aut | |
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