Targeting the insulin-like growth factor I receptor inhibits proliferation and VEGF production of non-small cell lung cancer cells and enhances paclitaxel-mediated anti-tumor effect.

Abstract

The effects of AVE1642, a human monoclonal antibody against IGF-IR, were examined in NSCLC cell lines in order to characterize its anti-proliferative and anti-angiogenic activity as a single agent and in combination with chemotherapy. AVE1642 inhibited IGF-IR signaling and suppressed IGF-I-induced, serum-stimulated or autocrine-mediated proliferation of NSCLC cells in vitro. Furthermore, the combination of paclitaxel and AVE1642 resulted in a sequence-dependent increase in the inhibition of cell proliferation, compared to each agent alone, which was associated with a dose-dependent increase in phosphorylated IGF-IR and Akt. Moreover, inhibition of IGF-IR signaling by AVE1642 reduced IGF-I-induced VEGF production by NSCLC cells as well as the migratory capacity of HUVEC cells challenged with conditioned media from lung cancer cells previously exposed to IGF-I. The above results suggest that inhibition of IGF-IR signaling by AVE1642 enhances the efficacy of chemotherapy and modulates VEGF and angiogenesis in NSCLC. These effects may have important clinical implications in the treatment of NSCLC.

• Authors: Maria Spiliotaki, Haris Markomanolaki, Marilena Mela, Dimitris Mavroudis, Vassilis Georgoulias, Sofia Agelaki
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 73 Issue 2 Pg. 158-65 (Aug 2011) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 21190751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Culture Media, Conditioned
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Mitogen-Activated Protein Kinases
• Paclitaxel
• AVE1642

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Carcinoma, Non-Small-Cell Lung
• Cell Line, Tumor (drug effects)
• Cell Movement
• Cell Proliferation (drug effects)
• Culture Media, Conditioned
• Drug Interactions
• Endothelial Cells (drug effects, physiology)
• Humans
• Insulin-Like Growth Factor I (pharmacology)
• Lung Neoplasms
• Mitogen-Activated Protein Kinases (metabolism)
• Paclitaxel (administration & dosage, pharmacology)
• Phosphorylation
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)