title: Not flavone-8-acetic acid (FAA) but its murine metabolite 6-OH-FAA exhibits remarkable antivascular activities in vitro.
abstract: Flavone-8-acetic acid (FAA) has been proved to be a potent vascular-disrupting agent in mice. Unfortunately, FAA did not produce any anticancer activity in clinical trials. Previously, we had reported that FAA is metabolized by mouse microsomes into six metabolites, whereas it was poorly metabolized by human microsomes, with fewer metabolites formed in lesser amounts. Especially, 6-OH-FAA was not formed by human microsomes. In this work, two major available metabolites, 4'-OH-FAA and 6-OH-FAA, were tested and compared with the parent compound FAA for their potential antivascular activities in vitro. The ability of the products to induce morphological changes, disrupt preformed capillaries of EA.hy926 endothelial cells and inhibit tubulin polymerization in vitro was assessed. The action mechanism was determined using the RhoA and Rac1 inhibitors. At 25 µg/ml, 6-OH-FAA induced morphological changes and membrane blebbing, whereas 300 µg/ml of FAA and 4'-OH-FAA slightly changed the morphology without inducing membrane blebbing. At 300 µg/ml, 6-OH-FAA produced morphological changes that were 2.1-6.9-fold greater than that produced by FAA and 4'-OH-FAA, an effect that was consistent with its much greater inhibitory effect on tubulin polymerization compared with FAA and 4'-OH-FAA. 6-OH-FAA significantly disrupted the EA.hy926 cell capillaries. 6-OH-FAA activities were prevented in EA.hy926 cells pretreated with RhoA, but not Rac1, inhibitor. In this short communication we report for the first time that, in vitro, 6-OH-FAA, a mouse-specific FAA metabolite, exhibits significantly stronger antivascular activities compared with FAA and 4'-OH-FAA, which are mediated through the RhoA kinase pathway.
authors.affiliation: aChemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151 bMedical Oncology and Cellular Therapy Department, Tenon Hospital, Public Assistance-Hospitals of Paris (APHP), Alliance for Cancer Research (APREC) cLaboratory of Therapeutic Drug Monitoring, Platform for Peptidomic, Metabolomic and Drug Measurements, Saint Antoine Hospital dDepartment of Research, Institute Curie, CNRS UMR3666, INSERM U1143, Paris, France.
authors.forename: Minh Hien
authors.initials: MH
authors.lastname: Pham
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
authors.forename: Guy G
authors.initials: GG
authors.lastname: Chabot
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D058105:Polymerization; D014404:Tubulin / Q000737:chemistry
chemical_list: C000609814:6-OH-FAA; D020533:Angiogenesis Inhibitors; D005419:Flavonoids; D014404:Tubulin; C049328:flavone acetic acid