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Emodin inhibits vascular endothelial growth factor‐A‐induced angiogenesis by blocking receptor‐2 (KDR/Flk‐1) phosphorylation
Author(s) -
Kwak HeeJin,
Park MyungJin,
Park ChangMin,
Moon SangIk,
Yoo DooHyun,
Lee HyungChahn,
Lee SeungHoon,
Kim MiSuk,
Lee HyeanWoo,
Shin WoonSeob,
Park InChul,
Rhee Chang Hun,
Hong SeokIl
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21641
Subject(s) - emodin , angiogenesis , microbiology and biotechnology , matrigel , vascular endothelial growth factor , kinase insert domain receptor , biology , vascular endothelial growth factor a , chemistry , cancer research , biochemistry , vegf receptors
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 G 0 /G 1 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 . © 2006 Wiley‐Liss, Inc.