Potent in Vivo Antiangiogenic Effects of GS-101 (5′-TATCCGGAGGGCTCGCCATGCTGCT-3′), an Antisense Oligonucleotide Preventing the Expression of Insulin Receptor Substrate-1

Angiogenesis is a complex phenomenon regulated by both pro- and antiangiogenic factors such as the vascular endothelial growth factor (VEGF), and inflammation may be involved in the process. Although antagonizing VEGF has been proposed as a therapeutic approach to limit corneal angiogenesis, alterna...

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Veröffentlicht in:The Journal of pharmacology and experimental therapeutics 2009-05, Vol.329 (2), p.496-504
Hauptverfasser: Al-Mahmood, Salman, Colin, Sylvie, Farhat, Nada, Thorin, Eric, Steverlynck, Céline, Chemtob, Sylvain
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Sprache:eng
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Zusammenfassung:Angiogenesis is a complex phenomenon regulated by both pro- and antiangiogenic factors such as the vascular endothelial growth factor (VEGF), and inflammation may be involved in the process. Although antagonizing VEGF has been proposed as a therapeutic approach to limit corneal angiogenesis, alternative targets are needed. In this study, we demonstrate that, under proangiogenic experimental conditions, human endothelial cells (hECs) express more insulin receptor substrate (IRS)-1 proteins relative to quiescent cells. The antisense oligonucleotide, GS-101 (5′-TATCCGGAGGGCTCGCCATGCTGCT-3′), targeting IRS-1 mRNA, dose-dependently inhibited ( p < 0.01) both IRS-1 expression and in vitro angiogenesis (hEC tube-like structure formation) with IC 50 of 8.51 ± 3.01 μM (mean ± S.E.M.) and 2.47 ± 0.56 μM, respectively, demonstrating that partial IRS-1 down-regulation interferes with angiogenesis. The antiangiogenic effects of GS-101 were associated with a decrease in protein kinase B (Akt) activation but not mitogen-activated protein kinase-1/2 and a dose-dependent reduction in vascular endothelial growth factor-A (IC 50 = 5.59 ± 2.76 μM) and the proinflammatory cytokine interleukin-1β (IC 50 = 2.19 ± 1.07 μM) mRNA expression. In accordance, once daily topical application of GS-101 dose-dependently inhibited injury-dependent corneal angiogenesis in vivo ( p < 0.05). GS-101 in vivo efficacy was achieved at final tissue concentrations within in vitro EC 50 for IRS-1 down-regulation. In conclusion, these results suggest that IRS-1 is important for angiogenesis and that GS-101 could become a novel therapeutic tool against corneal angiogenesis.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.108.147496