Research Papers:
A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras
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Abstract
Agnès Desroches-Castan1,2,3, Delphine Quélard1,2,3,4, Martine Demeunynck2,5, Jean-François Constant2,6, Chongling Dong2,6, Michelle Keramidas2,7, Jean-Luc Coll2,7, Caroline Barette2,3,8, Laurence Lafanechère2,3,7, Jean-Jacques Feige1,2,3
1Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1036, Biology of Cancer and Infection, Grenoble, F-38054, France
2Univ. Grenoble-Alpes, Department of Chemistry, Biology and Health Sciences, Grenoble, F-38000, France
3Commissariat à l'Energie Atomique (CEA), DSV/iRTSV, Grenoble, F-38054, France
4Janssen, Pharmaceutical Companies of Johnson and Johnson, Issy-les-Moulineaux, F-92130, France
5Centre National de la Recherche Scientifique (CNRS), UMR 5063, Department of Molecular Pharmacochemistry, Grenoble, F-38041, France
6Centre National de la Recherche Scientifique (CNRS), UMR 5250, Department of Molecular Chemistry, Grenoble, F-38041, France
7Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 823, Albert Bonniot Research Center, La Tronche, F-38700, France
8Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1038, Large Scale Biology, Grenoble, F-38054, France
Correspondence to:
Jean-Jacques Feige, e-mail: [email protected]
Keywords: angiogenesis, chemical library, VEGF signaling, drug development
Received: September 25, 2014 Accepted: December 19, 2014 Published: January 23, 2015
ABSTRACT
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.
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