Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway

Sei-Joon Jeong; Takashi Itokawa; Masabumi Shibuya; Michihiko Kuwano; Mayumi Ono; Ryuichi Higuchi; Tomofumi Miyamoto

doi:10.1016/s0304-3835(02)00361-0

Costunolide, a sesquiterpene lactone from Saussurea lappa, inhibits the VEGFR KDR/Flk-1 signaling pathway

Cancer Lett. 2002 Dec 10;187(1-2):129-33. doi: 10.1016/s0304-3835(02)00361-0.

Authors

Sei-Joon Jeong¹, Takashi Itokawa, Masabumi Shibuya, Michihiko Kuwano, Mayumi Ono, Ryuichi Higuchi, Tomofumi Miyamoto

Affiliation

¹ Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

PMID: 12359360
DOI: 10.1016/s0304-3835(02)00361-0

Abstract

Costunolide (CT), a sesquiterpene lactone constituent isolated from Saussurea lappa (Compositae), exerted an antiangiogenic effect. CT selectively inhibited the endothelial cell proliferation induced by vascular endothelial growth factor (VEGF). Further, CT was also found to inhibit the VEGF-induced chemotaxis of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. From these results, we hypothesized that CT might inhibit angiogenesis by blocking the angiogenic factor signaling pathway. VEGF interacts with its cognate receptors, KDR/Flk-1 and Flt-1, and exerts its angiogenic effect. CT inhibited the autophosphorylation of KDR/Flk-1 without affecting that of Flt-1. Moreover, administration of CT reduced VEGF-induced neovascularization in a mouse corneal micropocket assay. These results suggest that CT may prove useful for the development of a novel angiogenesis inhibitor.

MeSH terms

3T3 Cells
Angiogenesis Inhibitors / isolation & purification
Angiogenesis Inhibitors / pharmacology*
Animals
Cell Division / drug effects
Chemotaxis
Corneal Neovascularization / metabolism
Corneal Neovascularization / prevention & control*
Dose-Response Relationship, Drug
Endothelial Growth Factors / genetics
Endothelial Growth Factors / metabolism
Endothelium, Vascular / metabolism
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Lymphokines / genetics
Lymphokines / metabolism
Mice
Phosphorylation
Saussurea / chemistry*
Sesquiterpenes / isolation & purification
Sesquiterpenes / pharmacology*
Signal Transduction / drug effects*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2 / genetics
Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Vascular Endothelial Growth Factors

Substances

Angiogenesis Inhibitors
Endothelial Growth Factors
Intercellular Signaling Peptides and Proteins
Lymphokines
Sesquiterpenes
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
costunolide
Vascular Endothelial Growth Factor Receptor-2