title: Identification and biological activities of a new antiangiogenic small molecule that suppresses mitochondrial reactive oxygen species.
abstract: Mitochondrial reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. In particular, high levels of mitochondrial ROS in hypoxic cells regulate many angiogenesis-related diseases, including cancer and ischemic disorders. Here we report a new angiogenesis inhibitor, YCG063, which suppressed mitochondrial ROS generation in a phenotypic cell-based screening of a small molecule-focused library with an ArrayScan HCS reader. YCG063 suppressed mitochondrial ROS generation under a hypoxic condition in a dose-dependent manner, leading to the inhibition of in vitro angiogenic tube formation and chemoinvasion as well as in vivo angiogenesis of the chorioallantoic membrane (CAM) at non-toxic doses. In addition, YCG063 decreased the expression levels of HIF-1α and its target gene, VEGF. Collectively, a new antiangiogenic small molecule that suppresses mitochondrial ROS was identified. This new small molecule tool will provide a basis for a better understanding of angiogenesis driven under hypoxic conditions.
authors.affiliation: Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Ju Yeol
authors.initials: JY
authors.lastname: Park
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009593:Nitroimidazoles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries
chemical_list: D020533:Angiogenesis Inhibitors; D006835:Hydrazones; D009593:Nitroimidazoles; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; C555826:YCG 063