Abstract
The potential therapeutic value of combinatorial regimens based on an EGF receptor tyrosine kinase inhibitor (TKI) and autophagy inducing drugs was evaluated by comparing their molecular impacts on H1299 and A549 non-small cell lung cancer (NSCLC) cells, which overexpress wild type EGF receptor, but are either deficient or have wild type p53 alleles, respectively. We show that H1299 cells display a considerably lower sensitivity to erlotinib treatment, which can be restored by combining erlotinib with rapamycin or with imatinib, though to a lesser extent. Cytotoxicity was associated with increased autophagy and hyperpolarization of the mitochondrial membrane potential. Therefore, combining an EGF receptor directed TKI with an autophagy-inducing drug, preferably, rapamycin, might be beneficial in treating poor responding NSCLC patients.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Autophagy / drug effects
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Benzamides
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / enzymology
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Cycle / drug effects
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / biosynthesis
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Erlotinib Hydrochloride
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Humans
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Imatinib Mesylate
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Lung Neoplasms / pathology
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Membrane Potential, Mitochondrial / drug effects
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Piperazines / administration & dosage
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology
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Quinazolines / administration & dosage
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Quinazolines / pharmacology
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Sirolimus / administration & dosage
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Sirolimus / pharmacology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / deficiency
Substances
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Benzamides
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Quinazolines
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TP53 protein, human
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Tumor Suppressor Protein p53
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Imatinib Mesylate
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Erlotinib Hydrochloride
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ErbB Receptors
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Sirolimus