title: Inhibition of 5-lipoxygenase suppresses vascular endothelial growth factor-induced angiogenesis in endothelial cells.
abstract: 5-Lipoxygenase (5-LOX) is an enzyme that converts arachidonic acid from the cell membrane into leukotriene, a signal lipid mediator. 5-LOX deficiency markedly attenuates the formation of aneurysms in knockout mice. In addition, Zileuton, a clinical drug targeting 5-LOX, is used for treatment of asthma. However, it is unclear whether 5-LOX inhibition results in anti-angiogenic effects for applications in cancer therapy. To explore the roles of 5-LOX in angiogenesis and its potential as a therapeutic target in cancer, the effects of a newly synthesized 5-LOX inhibitor, F3, on in vitro and in vivo angiogenesis were investigated. The results showed that 5-LOX inhibition by F3 suppressed in vitro vascular endothelial growth factor (VEGF)-induced tube formation and chemo-invasion of endothelial cells (ECs). 5-LOX inhibition also decreased VEGF-induced extracellular signal-regulated kinase (ERK) phosphorylation in ECs. Notably, 5-LOX knockdown phenocopied the anti-angiogenic activity of the 5-LOX inhibitor F3 in a concentration-dependent manner. F3 did not affect the activities of VEGF receptor 2 or AKT. In vivo, the compound significantly inhibited the formation of the chorioallantoic membrane at nontoxic doses. These results demonstrated that 5-LOX played an important role in angiogenesis and that its inhibitor F3 could be a new anti-angiogenic agent targeting VEGF signaling.
authors.affiliation: Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Joohye
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Hea-Young Park
authors.initials: HY
authors.lastname: Choo
authors.affiliation: Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: kwonhj@yonsei.ac.kr.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002645:Chickens; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D016859:Lipoxygenase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D001094:Arachidonate 5-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: 5-Lipoxygenase; Anti-angiogenic effects; Vascular endothelial growth factor signaling