Inhibition of IGF1R enhances 2-deoxyglucose in the treatment of non-small cell lung cancer
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Date
2018
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Elsevier Ireland Ltd
Abstract
Objective: We previously postulated that 2-deoxyglucose (2-DG) activates multiple pro-survival pathways through IGF1R to negate its inhibitory effect on glycolysis. Here, we evaluated whether IGF1R inhibitor synergizes with 2-DG to impede the growth of non-small cell lung cancer (NSCLC). Materials and methods: The activation of IGF1R signaling was assessed by the phosphorylation of IGF1R and its downstream target AKT using immunoblot. Drug dose response and combination index analyses were carried out according to the method of Chou and Talalay. Flow cytometry was used to evaluate cell cycle progression. Apoptosis was monitored by caspase-3/PARP cleavages or Annexin V staining. A subcutaneous xenograft model was used to assess this combination in vivo. Results: 2-DG induces the phosphorylation of IGF1R in its kinase domain, which can be abolished by the IGF1R inhibitor BMS-754807. Furthermore, the combination of 2-DG and BMS-754807 synergistically inhibited the survival of several non-small cell lung cancer (NSCLC) cell lines both in vitro and in vivo. The mechanistic basis of this synergy was cell line-dependent, and LKB1-inactivated EKVX cells underwent apoptosis following treatment with a subtoxic dose of 2-DG and BMS-754807. For these cells, the restoration of LKB1 kinase activity suppressed apoptosis induced by this combination but enhanced G1 arrest. In H460 cells, the addition of 2-DG did not enhance the low level of apoptosis induced by BMS-754807. However, treatment with 0.75 μM of BMS-754807 resulted in the accumulation of H460 cells with 8n-DNA content without affecting cell density increases. Hence, H460 cells may escape BMS-754807-induced G2/M cell cycle arrest through polyploidy. The inclusion of 2-DG blocked formation of the 8n-DNA cell population and restored G2/M phase cell cycle arrest. Conclusion: The combination of 2-DG and IGF1R inhibitor BMS-754807 may be used to suppress the proliferation of NSCLC tumors through different mechanisms. © 2018 Elsevier B.V.
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Keywords
Cancer therapy, Energy metabolism, Insulin-like growth factor receptor 1 (igf1r), Lung cancer, Tumor suppressor gene, Animals, Apoptosis, Biomarkers, Carcinoma, non-small-cell lung, Cell cycle, Cell line, tumor, Deoxyglucose, Disease models, animal, Drug synergism, Humans, Lung neoplasms, Mice, Phosphorylation, Protein kinase inhibitors, Protein-serine-threonine kinases, Pyrazoles, Receptors, somatomedin, Triazines, Xenograft model antitumor assays, 1 [4 [(5 cyclopropyl 1h pyrazol 3 yl)amino]pyrrolo[2,1 f][1,2,4]triazin 2 yl] n (6 fluoro 3 pyridinyl) 2 methyl 2 pyrrolidinecarboxamide, Caspase 3, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, Protein kinase b, Somatomedin c receptor, Biological marker, Igf1r protein, human, Protein kinase inhibitor, Protein serine threonine kinase, Pyrazole derivative, Somatomedin receptor, Stk11 protein, human, Triazine derivative, Animal experiment, Animal model, Animal tissue, Article, Cancer inhibition, Cell cycle progression, Controlled study, Drug potentiation, Female, Flow cytometry, G1 phase cell cycle checkpoint, G2 phase cell cycle checkpoint, Human, Human cell, Immunoblotting, In vitro study, In vivo study, Mouse, Nci-h157 cell line, Nci-h460 cell line, Non small cell lung cancer, Nonhuman, Polyploidy, Priority journal, Protein phosphorylation, Signal transduction, Survival, Tumor xenograft, Animal, Antagonists and inhibitors, Disease model, Drug effect, Drug screening, Lung tumor, Metabolism, Tumor cell line