title: Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation.
abstract: Emodin (1,3,8-trihydroxy-6-methylanthraquinone), an active component in the root and rhizome of Rheum palmatum, is a tyrosine kinase inhibitor with a number of biological activities, including antitumor effects. Here, we examine the effects of emodin on vascular endothelial growth factor (VEGF)-A-induced angiogenesis, both in vitro and in vivo. In vitro, emodin dose-dependently inhibits proliferation, migration into the denuded area, invasion through a layer of Matrigel and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated with VEGF-A. Emodin also inhibits basic fibroblast growth factor-induced proliferation and migration of HUVECs and VEGF-A-induced tube formation of human dermal microvascular endothelial cells. Specifically, emodin induces the cell cycle arrest of HUVECs in the G0/G1 phase by suppressing cyclin D1 and E expression and retinoblastoma protein phosphorylation, and suppresses Matrigel invasion by inhibiting the basal secretion of matrix metalloproteinase-2 and VEGF-A-stimulated urokinase plasminogen activator receptor expression. Additionally, emodin effectively inhibits phosphorylation of VEGF-A receptor-2 (KDR/Flk-1) and downstream effector molecules, including focal adhesion kinase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, Akt and endothelial nitric oxide synthase. In vivo, emodin strongly suppresses neovessel formation in the chorioallantoic membrane of chick and VEGF-A-induced angiogenesis of the Matrigel plug in mice. Our data collectively demonstrate that emodin effectively inhibits VEGF-A-induced angiogenesis in vitro and in vivo. Moreover, inhibition of phosphorylation of KDR/Flk-1 and downstream effector molecules is a possible underlying mechanism of the anti-angiogenic activity of emodin. Based on these data, we propose that an interaction of emodin with KDR/Flk-1 may be involved in the inhibitory function of emodin toward VEGF-A-induced angiogenesis in vitro and responsible for its potent anti-angiogenic in vivo.
authors.affiliation: Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kwak
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Park
authors.forename: Sang-Ik
authors.initials: SI
authors.lastname: Moon
authors.forename: Doo-Hyun
authors.initials: DH
authors.lastname: Yoo
authors.forename: Hyung-Chahn
authors.initials: HC
authors.lastname: Lee
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Mi-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Hyean-Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Woon-Seob
authors.initials: WS
authors.lastname: Shin
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Rhee
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004642:Emodin / Q000494:pharmacology*; D042783:Endothelial Cells; D006801:Humans; D007797:Laminin; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010766:Phosphorylation; D011509:Proteoglycans; D014470:Umbilical Cord / Q000098:blood supply; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D001672:Biocompatible Materials; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2; D004642:Emodin