Inhibition de l’angiogenèse tumorale : criblage d’une chimiothèque et caractérisation d’un nouveau composé agissant sur la voie de signalisation Ras-ERK

Abstract : Several anti-tumoral therapies targeting angiogenesis have been developed over the recent years and have demonstrated benefits for several metastatic cancers. However, in many cases, resistances to these treatments appear over time, allowing tumor escape. The development of new anti-angiogenic compounds is thus dramatically urged in order to propose second-line anti-angiogenic treatments. In this work, our aim was to identify new anti-angiogenic compounds through high throughput screening of the academic library from the University of Grenoble. We adapted the endothelial cell scratch assay to 96-well plates. We identified a family of molecules that specifically inhibited endothelial cell migration. The anti-angiogenic activity of the leader molecule (COB223) was confirmed in vitro in 3D cellular models of angiogenesis and in vivo using a mouse model of subcutaneous sponge implantation. We tested the anti-tumoral activity of COB223 on a mouse xenograft model. We observed that tumor growth was significantly reduced in treated mice correlated with decreased microvessel density. In search for its mechanism of action, we observed that COB223 inhibits cell proliferation and reduces VEGF-A-induced phosphorylation of MEK and ERK1/2 in endothelial cells. We also showed that COB223 did not affect VEGFR2 and PLCgamma phosphorylation but reduces Raf phosphorylation responsible for its activity. These results allow us to propose that the molecular site of action of COB223 is located in the VEGF/ PLCgamma /PKC/ERK pathway, between PKC and MEK.
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Agnès Desroches-Castan. Inhibition de l’angiogenèse tumorale : criblage d’une chimiothèque et caractérisation d’un nouveau composé agissant sur la voie de signalisation Ras-ERK. Biologie cellulaire. Université Joseph Fourier, 2014. Français. ⟨tel-01116053⟩

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