title: Organometallic ruthenium(II) arene compounds with antiangiogenic activity.
abstract: The antimetastatic ruthenium(II) compounds [Ru(η(6)-p-cymene)Cl(2)(PTA)] (PTA = 1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) and [Ru(η(6)-toluene)Cl(2)(PTA)] (RAPTA-T), as well as their analogues [Ru(η(6)-p-cymene)Cl(2)(DAPTA)] (DAPTA = (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)) (DAPTA-C) and [Ru(η(6)-toluene)Cl(2)(DAPTA)] (DAPTA-T), respectively, were tested in in vitro bioassays for endothelial cell function. All compounds showed low toxicity profiles and similar dose-dependent antiproliferative effects in endothelial cells at ≥100 μg/mL (∼200 μM). EC migration, measured 6 h after drug exposure, was also efficiently inhibited (ED(50) of ∼300 μg/mL, ∼500 μM, for all compounds). Since no cytostatic effect was noted, the inhibition of proliferation was considered mainly to consist of antiangiogenic activity. RAPTA-T and DAPTA-C were also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit CAM development. Importantly, effective prevention of revascularization of the CAM after vaso-occlusive photodynamic therapy was observed. The reported ruthenium complexes show promising antimetastatic activity involving inhibition of angiogenesis and therefore are attractive agents for development of anticancer therapies based on combination of chemo- and angiostatic treatments.
authors.affiliation: Institute of Bio-Engineering, Swiss Federal Institute of Technology, Lausanne, Switzerland. patrycja.nowak-sliwinska@epfl.ch
authors.forename: Patrycja
authors.initials: P
authors.lastname: Nowak-Sliwinska
authors.forename: Judy R
authors.initials: JR
authors.lastname: van Beijnum
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Nazarov
authors.forename: Georges
authors.initials: G
authors.lastname: Wagnieres
authors.forename: Hubert
authors.initials: H
authors.lastname: van den Bergh
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects; D000081007:Cymenes; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010778:Photochemotherapy; D012428:Ruthenium / Q000633:toxicity
chemical_list: D020533:Angiogenesis Inhibitors; D000081007:Cymenes; D009942:Organometallic Compounds; C534678:RAPTA-T; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); D012428:Ruthenium