A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras
The efficacy of anti-angiogenic therapies on cancer patients is limited by the emergence of drug resistance, urging the search for second-generation drugs. In this study, we screened an academic chemical library (DCM, University of Grenoble-Alpes) and identified a leader molecule, COB223, that inhibits endothelial cell migration and proliferation. It inhibits also Lewis lung carcinoma (LLC/2) cell proliferation whereas it does not affect fibroblast proliferation. The anti-angiogenic activity of COB223 was confirmed using several in vitro and in vivo assays. In a mouse LLC/2 tumor model, ip administration of doses as low as 4 mg/kg COB223 efficiently reduced the tumor growth rate. We observed that COB223 inhibits endothelial cell ERK1/2 phosphorylation induced by VEGF, FGF-2 or serum and that it acts downstream of PKC and upstream of Ras. This molecule represents a novel anti-angiogenic and anti-tumorigenic agent with an original mechanism of action that deserves further development as an anti-cancer drug.[on SciFinder (R)]
Références
- Titre
- A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras
- Type de publication
- Article de revue
- Année de publication
- 2015
- Auteurs
- Desroches-Castan, Agnes, Quelard Delphine, Demeunynck Martine, Constant Jean-François, Dong Chongling, Keramidas Michelle, Coll Jean-Luc, Barette Caroline, Lafanechere Laurence, and Feige Jean-Jacques
- Revue
- Oncotarget
- Volume
- 6
- Pagination
- 5382–5411
- ISSN
- 1949-2553
Soumis le 18 mai 2018