PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PURPOSE: 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. MATERIALS AND METHODS:Humanlung 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. RESULTS: 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. CONCLUSION: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.