title: Antitumour activity of the novel flavonoid Oncamex in preclinical breast cancer models.
abstract: BACKGROUND
  The natural polyphenol myricetin induces cell cycle arrest and apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with enhanced redox properties, improved cell uptake and mitochondrial targeting might have increased potential as antitumour agents.
  
  
  METHODS
  We studied the effect of a second-generation flavonoid analogue Oncamex in a panel of seven breast cancer cell lines, applying western blotting, gene expression analysis, fluorescence microscopy and immunohistochemistry of xenograft tissue to investigate its mechanism of action.
  
  
  RESULTS
  Proliferation assays showed that Oncamex treatment for 8 h reduced cell viability and induced cytotoxicity and apoptosis, concomitant with increased caspase activation. Microarray analysis showed that Oncamex was associated with changes in the expression of genes controlling cell cycle and apoptosis. Fluorescence microscopy showed the compound's mitochondrial targeting and reactive oxygen species-modulating properties, inducing superoxide production at concentrations associated with antiproliferative effects. A preliminary in vivo study in mice implanted with the MDA-MB-231 breast cancer xenograft showed that Oncamex inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no signs of untoward effects on the animals.
  
  
  CONCLUSIONS
  Oncamex is a novel flavonoid capable of specific mitochondrial delivery and redox modulation. It has shown antitumour activity in preclinical models of breast cancer, supporting the potential of this prototypic candidate for its continued development as an anticancer agent.
authors.affiliation: Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Pérez
authors.affiliation: Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Ward
authors.affiliation: Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Arran K
authors.initials: AK
authors.lastname: Turnbull
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Mullen
authors.affiliation: Antoxis Limited, IMS Building, Foresterhill Health and Research Complex, Aberdeen AB25 2ZD, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Cook
authors.affiliation: Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: James
authors.initials: J
authors.lastname: Meehan
authors.affiliation: Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Jarman
authors.affiliation: EaSTCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, Edinburgh EH9 3FJ, UK.
authors.forename: Patrick I T
authors.initials: PI
authors.lastname: Thomson
authors.affiliation: EaSTCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, Edinburgh EH9 3FJ, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Campbell
authors.affiliation: Antoxis Limited, IMS Building, Foresterhill Health and Research Complex, Aberdeen AB25 2ZD, UK.
authors.forename: Donald
authors.initials: D
authors.lastname: McPhail
authors.affiliation: School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D017382:Reactive Oxygen Species; C040015:myricetin