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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Authors: | Kiyoaki Yonesu Yumi Kawase Nana Takagi Yoh Takuwa Futoshi Nara |
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Affiliation: | a Exploratory Research Laboratories II, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan b Biological Research Laboratories II, Daiichi Sankyo Co., Ltd., Japan c Biological Research Laboratories III, Daiichi Sankyo Co., Ltd., Japan d Intellectual Property Department, Daiichi Sankyo Co., Ltd., Japan e Department of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan |
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Abstract: | 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. |
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Keywords: | bFGF, basic fibroblast growth factor CHO, Chinese hamster ovary CL2, chemical lead 2 dhfr, dihydrofolate reductase Edg-1/S1P1, endothelial differentiation gene-1 FBS, fetal bovine serum FLIPR, fluorometric imaging plate reader HEK293, human embryonic kidney 293 homo KO, homozygous knockout HUVEC, human umbilical vein endothelial cells IBMX, 3-isobutyl-1-methylxanthine LPS, lipopolysaccharide MTX, methotrexate NZW, New Zealand white Sph-1-P, sphingosine-1-phosphate VEGF, vascular endothelial growth factor |
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