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Capsiate, a Nonpungent Capsaicin-Like Compound, Inhibits Angiogenesis and Vascular Permeability via a Direct Inhibition of Src Kinase Activity

¹ Department of Biochemistry, College of Sciences, Yonsei University; ² College of Pharmacy and National Core Research Center for Cell Signaling and Drug Discovery, Ewha Womans University; ³ Department of Plant Science, College of Agriculture and Life Sciences and ⁴ School of Agricultural Biotechnology, Seoul National University; ⁵ Laboratory of Dermatology-Immunology, Catholic Research Institute of Medical Science, Catholic University, Seoul, South Korea; ⁶ Department of Biochemistry, College of Natural Sciences and ⁷ Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chunchon, South Korea; and ⁸ Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea

Requests for reprints: Young-Guen Kwon, Department of Biochemistry, College of Sciences, Yonsei University, Seoul, 120-749, South Korea. Phone: 82-2-2123-5697; Fax: 82-2-362-9897; E-mail: ygkwon{at}yonsei.ac.kr.

Capsiate, a nonpungent capsaicin analogue, and its dihydroderivative dihydrocapsiate are the major capsaicinoids of the nonpungent red pepper cultivar CH-19 Sweet. In this study, we report the biological actions and underlying molecular mechanisms of capsiate on angiogenesis and vascular permeability. In vitro, capsiate and dihydrocapsiate inhibited vascular endothelial growth factor (VEGF)–induced proliferation, chemotactic motility, and capillary-like tube formation of primary cultured human endothelial cells. They also inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessels in the mouse Matrigel plug assay in response to VEGF. Moreover, both compounds blocked VEGF-induced endothelial permeability and loss of vascular endothelial (VE)–cadherin–facilitated endothelial cell-cell junctions. Importantly, capsiate suppressed VEGF-induced activation of Src kinase and phosphorylation of its downstream substrates, such as p125^FAK and VE-cadherin, without affecting autophosphorylation of the VEGF receptor KDR/Flk-1. In vitro kinase assay and molecular modeling studies revealed that capsiate inhibits Src kinase activity via its preferential docking to the ATP-binding site of Src kinase. Taken together, these results suggest that capsiate could be useful for blocking pathologic angiogenesis and vascular permeability caused by VEGF. [Cancer Res 2008;68(1):227–35]