Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530, Japan.
Biochem Biophys Res Commun. 2012 Mar 23;419(4):754-60. doi: 10.1016/j.bbrc.2012.02.096. Epub 2012 Feb 24.
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.
鞘氨醇 1-磷酸受体 1（S1P1）在胚胎发育过程中对血管成熟至关重要，并且已经证明 S1P1 与其他促血管生成生长因子（如血管内皮生长因子 [VEGF] 和碱性成纤维细胞生长因子）之间存在大量的相互作用。我们开发了一种新型的 S1P1 选择性拮抗剂 TASP0277308，它在结构上与 S1P 以及以前描述的 S1P1 拮抗剂无关。TASP0277308 抑制 S1P 以及 VEGF 诱导的细胞反应，包括人脐静脉内皮细胞的迁移和增殖。此外，TASP0277308 可有效阻断 VEGF 诱导的体外管形成，并显著抑制肿瘤细胞诱导的体内血管生成。这些发现表明 S1P1 是 VEGF 相关血管生成反应的关键组成部分，也为 TASP0277308 用于癌症治疗的疗效提供了证据。
