title: Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Leão
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Soares
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Gomes
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Raimundo
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Ramos
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Bessa
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal.
authors.forename: Glória
authors.initials: G
authors.lastname: Queiroz
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal; Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Domingos
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal; Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal.
authors.forename: Madalena
authors.initials: M
authors.lastname: Pinto
authors.affiliation: CIBIO, Centre for Integrative Biology, Laboratory of Transcriptional Networks, University of Trento, Via delle Regole, 101 38123 Trento, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.affiliation: Centro de Química Medicinal da Universidade do Porto (CEQUIMED-UP), Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal; Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal.
authors.forename: Honorina
authors.initials: H
authors.lastname: Cidade
authors.affiliation: UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira no. 164, 4050-313 Porto, Portugal. Electronic address: lucilia.saraiva@ff.up.pt.
authors.forename: Lucília
authors.initials: L
authors.lastname: Saraiva
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D047188:Chalcones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Anticancer; Chalcones; Prenylation; Tumour cytotoxicity; p53–MDM2 interaction