title: Blocking S1P interaction with S1P₁ receptor by a novel competitive S1P₁-selective antagonist inhibits angiogenesis.
abstract: Sphingosine 1-phosphate receptor type 1 (S1P(1)) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P(1) and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P(1)-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P(1) antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P(1) is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.
authors.affiliation: Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530, Japan. y.fujii@po.rd.taisho.co.jp
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujii
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Ueda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohtake
authors.forename: Naoya
authors.initials: N
authors.lastname: Ono
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takayama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Ryo
authors.initials: R
authors.lastname: Goitsuka
mesh_terms: D045744:Cell Line, Tumor; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013450:Sulfones / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D013450:Sulfones; C569989:TASP0277308; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; C060506:sphingosine 1-phosphate; D013110:Sphingosine