A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras

Oncotarget. 2015 Mar 10;6(7):5382-411. doi: 10.18632/oncotarget.2979.

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.

Keywords: VEGF signaling; angiogenesis; chemical library; drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Carbamates / chemical synthesis
  • Carbamates / pharmacology*
  • Carcinoma, Lewis Lung / blood supply
  • Carcinoma, Lewis Lung / pathology
  • Carcinoma, Lewis Lung / prevention & control*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects*
  • High-Throughput Screening Assays
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects
  • Skin / cytology
  • Skin / drug effects
  • Skin / metabolism
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays
  • ras Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • COB223
  • Carbamates
  • Sulfonamides
  • Vascular Endothelial Growth Factor A
  • ras Proteins