Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation
| Autor: | Mi-Suk Kim, Chang-Min Park, Hee-Jin Kwak, In-Chul Park, Myung-Jin Park, Sang-Ik Moon, Seung Hoon Lee, Woon-Seob Shin, Hyean-Woo Lee, Chang Hun Rhee, Doo-Hyun Yoo, Seok-Il Hong, Hyung-Chahn Lee |
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| Rok vydání: | 2006 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Emodin Angiogenesis Receptor expression Biocompatible Materials Biology Umbilical Cord Mice chemistry.chemical_compound Cell Movement Animals Humans Neoplasm Invasiveness Phosphorylation Protein kinase B Cell Proliferation Matrigel Dose-Response Relationship Drug Neovascularization Pathologic Cell Cycle Endothelial Cells Vascular Endothelial Growth Factor Receptor-2 Cell biology Vascular endothelial growth factor Drug Combinations Vascular endothelial growth factor A Oncology chemistry Biochemistry Fms-Like Tyrosine Kinase 3 Proteoglycans Collagen Laminin |
| Zdroj: | International Journal of Cancer. 118:2711-2720 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.21641 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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