Anti-angiogenic properties of a sulindac analogue

A. Pyriochou, S. Tsigkos, T. Vassilakopoulos, T. Cottin, Z. Zhou, E. Gourzoulidou, C. Roussos, H. Waldmann, A. Giannis, Andreas Papapetropoulos

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Background and purpose: Angiopoietins (Ang) are crucial for new blood vessel formation and exert their effects by acting on the Tie2 receptor. We have recently described a sulindac analogue 2-((1E,Z)-1-benzylidene-5-bromo-2- methyl-1H-inden-3-yl)acetic acid; termed C-18 from now onwards) that inhibits Tie2 receptor activity in kinase assays in vitro. Here, we have assessed the ability of C-18 to inhibit angiogenesis-related properties of endothelial cells and tested its selectivity for the Tie2 receptor. Experimental approach: For in vitro experiments human umbilical vein endothelial cells (HUVEC) were used. Proliferation was measured using the MTT assay; migration assays were performed in a modified Boyden chamber and tube-like structure formation was determined on matrigel. The effects of C-18 in vivo were evaluated in the chicken chorioallantoic membrane (CAM). Key results: Pre-treatment of HUVEC with C-18 blocked Ang-1-stimulated migration, but also abolished vascular endothelial cell growth factor (VEGF)- and fibroblast growth factor 2-induced responses. Incubation with C-18 inhibited serum-induced proliferation in a concentration-dependent manner; C-18 was, however, without effect on Ang-1-induced survival. In addition, we observed that C-18 did not inhibit ligand-induced receptor phosphorylation of Tie2 or VEGFR2. On the other hand, C-18 blocked activation of members of the mitogen-activated protein kinase family and of the Ser/Thr kinase Akt induced by both VEGF and Ang-1. Furthermore, incubation of CAMs with C-18 led to a dose-dependent inhibition of vascular length. Conclusions and implications: C-18 did not act as a Tie2 inhibitor, as originally thought, but rather inhibited growth factor-stimulated signalling pathways that regulate endothelial cell migration and potently reduces neovascularization in vivo.

Original languageEnglish (US)
Pages (from-to)1207-1214
Number of pages8
JournalBritish Journal of Pharmacology
Volume152
Issue number8
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Keywords

  • Angiogenesis
  • Angiopoietin
  • MAPK
  • Migration
  • Sulindac
  • Tie2

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Pyriochou, A., Tsigkos, S., Vassilakopoulos, T., Cottin, T., Zhou, Z., Gourzoulidou, E., Roussos, C., Waldmann, H., Giannis, A., & Papapetropoulos, A. (2007). Anti-angiogenic properties of a sulindac analogue. British Journal of Pharmacology, 152(8), 1207-1214. https://doi.org/10.1038/sj.bjp.0707534