Abstract
Recent evidence indicates that both the phosphatidylinositol 3-kinase (PI3K)/AKT and the MEK/ERK pathways are strictly regulated by epidermal growth factor receptor in non-small cell lung cancer (NSCLC) that responds to Gefitinib. Gefitinib resistance is partly owing to the activation of two major downstream signaling pathways PI3K/AKT or MEK/ERK. In this study, we found that in Gefitinib-sensitive cell lines, Gefitinib could induce tumor cell apoptosis via upregulation of a proapoptotic protein BIM. Small interfering RNA results showed that silencing of BIM could alleviate apoptosis induced by Gefitinib. We adopted a combination of PI3K inhibitor (LY294002) and MEK inhibitor (U0126) against Gefitinib resistance in cell lines. As expected, the combination substantially induced apoptosis and restored the sensitivity to Gefitinib by increasing the expression of BIM. Our studies provided a theoretical basis for overcoming drug resistance in NSCLC via combination therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm*
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Enzyme Inhibitors / pharmacology
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Flow Cytometry
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Gefitinib
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Humans
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Immunoenzyme Techniques
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / metabolism
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology*
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RNA, Small Interfering / genetics
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Tumor Cells, Cultured
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Enzyme Inhibitors
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Membrane Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Quinazolines
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RNA, Small Interfering
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Proto-Oncogene Proteins c-akt
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MAP Kinase Kinase Kinases
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Gefitinib