title: 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.affiliation: Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Spiliotaki
authors.forename: Haris
authors.initials: H
authors.lastname: Markomanolaki
authors.forename: Marilena
authors.initials: M
authors.lastname: Mela
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mavroudis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
authors.forename: Sofia
authors.initials: S
authors.lastname: Agelaki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D017077:Culture Media, Conditioned; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008175:Lung Neoplasms; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; C545477:AVE1642