Angiogenesis inhibitor SR 25989 upregulates thrombospondin-1 expression in human vascular endothelial cells and foreskin fibroblasts.
The aim of this work was to evaluate the effects of SR 25989, a member of the thienopyridine family devoid of antiplatelet activity but possessing anti-angiogenic properties, on the regulation of proteins involved in matrix remodeling during wound healing or tumor progression. Human endothelial cells grown in the presence of SR 25989 showed moderate increases in the production of activators (tissue plasminogen activator and urokinase) and one inhibitor (plasminogen activator inhibitor type 1) of fibrinolysis, together with a significant rise in intracellular thrombospondin-1. SR 25989 induced a similar increase in thrombospondin-1 in human foreskin fibroblasts. This over-expression of thrombospondin-1 was correlated to a decrease in cell density. A concomitant increase in the tumor suppressor gene protein p53 was observed in endothelial cells and in fibroblasts, in which the slowing down of proliferation could be related to an accumulation of cells in the S and G2/M phases of the cell cycle. Northern blot analysis revealed a temporary rise in thrombospondin-1 transcripts, followed by a decrease along with a moderate increase in p53 transcripts. Thus the anti-angiogenic properties of SR 25989 appear to result from an upregulation of thrombospondin-1 which is possibly mediated by p53. The thienopyridine SR 25989 could therefore be a good candidate for adjuvant anti-angiogenic therapy in cancer.
Klein-Soyer
C
C
INSERM U311, Etablissement de Transfusion Sanguine de Strasbourg, France.
Céraline
J
J
Orvain
C
C
de la Salle
C
C
Bergerat
J P
JP
Cazenave
J P
JP
D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D000077144:Clopidogrel; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000096:biosynthesis; D006801:Humans; D018919:Neovascularization, Physiologic; D015676:Osteonectin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D019063:Tenascin / Q000096:biosynthesis; D019700:Thrombospondin 1 / Q000096:biosynthesis*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation
D005353:Fibronectins; D015676:Osteonectin; D012333:RNA, Messenger; D019063:Tenascin; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D012710:Serum Albumin, Bovine; D000077144:Clopidogrel; D013988:Ticlopidine