title: Inhibiting IGF-1R attenuates cell proliferation and VEGF production in IGF-1R over-expressing EGFR mutant non-small cell lung cancer cells.
abstract: The aim of the present study was to demonstrate the role of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitors (TKIs) in IGF-1R expressed epidermal growth factor receptor (EGFR) mutant cells.
  
  
  
  Human lung adenocarcinoma PC9, HCC827, and H1975 cells were exposed to a combination of IGF-1, gefitinib, or linsitinib. Cell viability was assessed by the MTT assay. The expression of EGFR, IGF-1R, AKT, extracellular regulated kinases 1 and 2 (ERK1/2), cleaved poly ADP ribose polymerase (PARP), cleaved caspase 3, and hypoxia-inducible factor (HIF)-1α were measured by Western blot. The concentrations of vascular endothelial growth factor (VEGF) were measured using an enzyme-linked immunosorbent assay kit.
  
  
  
  Cell growth in PC9 and HCC827 cells was synergistically suppressed by co-treatment with gefitinib and linsitinib. Gefitinib did not affect H1975 cell growth; however, linsitinib suppressed cell proliferation. Co-treatment with gefitinib and linsitinib inhibited pAKT and pERK, and linsitinib treatment profoundly reduced IGF-1-induced pIGF-1R expression in PC9 and HCC827 cells. Dual treatment increased the number of Annexin-V-positive HCC827 and H1975 cells, and expression of cleaved caspase 3 and cleaved PARP increased in H1975 cells following linsitinib treatment. Gefitinib inhibited HIF-1α and VEGF expression in HCC827 cells, and linsitinib inhibited VEGF production in H1975 cells.
  
  
  
  IGF-1R TKIs had modest anti-tumor efficacy and their effects were explained by blocking the EGFR and IGF-1R pathway in IGF-1R expressing EGFR-sensitive cells. IGF-1R TKI had pro-apoptotic activity and inhibited cellular growth in EGFR-resistant cells.
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Chang Dong
authors.initials: CD
authors.lastname: Yeo
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Kim
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Sang Haak
authors.initials: SH
authors.lastname: Lee
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Soon Seog
authors.initials: SS
authors.lastname: Kwon
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Kim
authors.affiliation: a Division of Pulmonology , Department of Internal Medicine , College of Medicine, The Catholic University of Korea , Seoul , Republic of Korea.
authors.forename: Seok Chan
authors.initials: SC
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: EGFR mutation; IGF-1R; VEGF