Involvement of sphingosine-1-phosphate and S1P1 in angiogenesis: analyses using a new S1P1 antagonist of non-sphingosine-1-phosphate analog.
Chemical lead 2 (CL2) is the first non-sphingosine-1-phosphate (Sph-1-P) analog type antagonist of endothelial differentiation gene-1 (Edg-1/S1P(1)), which is a member of the Sph-1-P receptor family. CL2 inhibits [(3)H]Sph-1-P/S1P(1) binding and shows concentration-dependent inhibition activity against both intracellular cAMP concentration decrease and cell invasion induced by the Sph-1-P/S1P(1) 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/S1P(1) 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/S1P(1) pathway in rheumatoid arthritis, diabetes retinopathy, and solid tumor growth processes.
Yonesu
Kiyoaki
K
Exploratory Research Laboratories II, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. yonesu.kiyoaki.t8@daiichisankyo.co.jp
Kawase
Yumi
Y
Inoue
Tatsuya
T
Takagi
Nana
N
Tsuchida
Jun
J
Takuwa
Yoh
Y
Kumakura
Seiichiro
S
Nara
Futoshi
F
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology
D020533:Angiogenesis Inhibitors; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine