Abstract
Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be regulated by the epidermal growth factor (EGF) signaling pathway. In this study, recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter (AdTRAIL) was combined with drugs including gefitinib, elotinib, and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer (NSCLC) cell lines to investigate their antitumor activity. In vitro, compared to single reagent, AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460, A549, and SW1573 cell lines. Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT. In vivo, AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice. Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL. These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.
MeSH terms
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Adenoviridae / genetics
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Apoptosis*
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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 Line, Tumor
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Cell Proliferation
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Cetuximab
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Drug Synergism
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ErbB Receptors / antagonists & inhibitors*
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Erlotinib Hydrochloride
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Female
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Gefitinib
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Genetic Therapy
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Genetic Vectors
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Humans
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Mice
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Mice, Nude
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
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TNF-Related Apoptosis-Inducing Ligand / physiology
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Transfection
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Tumor Burden
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Xenograft Model Antitumor Assays
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bcl-2-Associated X Protein / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Quinazolines
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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bcl-2-Associated X Protein
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Erlotinib Hydrochloride
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Cetuximab
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Gefitinib