Τίτλος:
Anti-angiogenic properties of a sulindac analogue
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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-3yl) 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.
Συγγραφείς:
Pyriochou, A.
Tsigkos, S.
Vassilakopoulos, T.
Cottin, T. and
Zhou, Z.
Gourzoulidou, E.
Roussos, C.
Waldmann, H. and
Giannis, A.
Papapetropoulos, A.
Περιοδικό:
British Journal of Pharmacology
Λέξεις-κλειδιά:
angiogenesis; Tie2; angiopoietin; sulindac; migration; MAPK
DOI:
10.1038/sj.bjp.0707534
