Involvement of sphingosine-1-phosphate and S1P₁ in angiogenesis: Analyses using a new S1P₁ antagonist of non-sphingosine-1-phosphate analog

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• 作者：Kiyoaki Yonesu ; Yumi Kawase ; Tatsuya Inoue ; Nana Takagi ; Jun Tsuchida ; Yoh Takuwa ; Seiichiro Kumakura ; Futoshi Nara
• 关键词：Angiogenesis inhibitor ; Sphingosine-1-phosphate (Sph-1-P) ; Endothelial differentiation gene-1 (Edg-1/S1P₁) ; Tube formation ; Anti-arthritis
• 刊名：Biochemical Pharmacology
• 出版年：2009
• 出版时间：15 March 2009
• 年：2009
• 卷：77
• 期：6
• 页码：1011-1020
• 全文大小：897 K

文摘

Chemical lead 2 (CL2) is the first non-sphingosine-1-phosphate (Sph-1-P) analog type antagonist of endothelial differentiation gene-1 (Edg-1/S1P₁), which is a member of the Sph-1-P receptor family. CL2 inhibits [³H]Sph-1-P/S1P₁ binding and shows concentration-dependent inhibition activity against both intracellular cAMP concentration decrease and cell invasion induced by the Sph-1-P/S1P₁ pathway. It also inhibits normal tube formation in an angiogenesis culture model, indicating that CL2 has anti-angiogenesis activity. This compound improved the disease conditions in two angiogenic models in vivo. It significantly inhibited angiogenesis induced by vascular endothelial growth factor in a rabbit cornea model as well as the swelling of mouse feet in an anti-type II collagen antibody-induced arthritis model. These results indicate that the Sph-1-P/S1P₁ pathway would have an important role in disease-related angiogenesis, especially in the processes of migration/invasion and tube formation. In addition, CL2 would be a powerful tool for the pharmacological study of the mechanisms of the Sph-1-P/S1P₁ pathway in rheumatoid arthritis, diabetes retinopathy, and solid tumor growth processes.