| Erlotinib activates mitochondrial death pathways related to the production of reactive oxygen species in the human non-small cell lung cancer cell line A549. | |
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MedLine Citation:
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PMID: 19673930 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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1. Erlotinib, a small-molecule epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, has been approved for the management of advanced non-small cell lung cancer. The aim of the present study was to investigate whether erlotinib exerts potent antitumour activities through the reactive oxygen species (ROS)-c-Jun N-terminal kinase (JNK) pathway in the human non-small cell lung cancer cell line A549. 2. The 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and Hoechst 33342 staining showed that erlotinib produced a decline in cell viability of A549 cells and induced cell apoptosis, coupled with quick accumulation of ROS. In addition, erlotinib increased the respiratory control ratio, NADPH oxidase catalytic subunit gp91(phox) expression and superoxide anion (O2(-)) generation, suggesting that erlotinib induced ROS production in A549 cells from both mitochondrial and NADPH oxidase sources. 3. Fluorescence microscopy with the JC-1 probe and western blot analysis indicated that erlotinib induced loss of mitochondrial membrane potential, the release of cytochrome c and apoptosis-inducing factor (AIF) and activation of JNK. 4. The results of the present study suggest that erlotinib has potent antitumour activity in A549 cells by activating ROS-dependent, JNK-driven cell apoptosis. These findings provide a novel insight into the mechanism of action of erlotinib in the treatment of human non-small cell lung cancer in addition to its effects in inhibiting EGFR-TK. |
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Authors:
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Xia Qian; Jing Li; Jianhua Ding; Zhiyuan Wang; Wenjing Zhang; Gang Hu |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-10-08 |
Journal Detail:
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Title: Clinical and experimental pharmacology & physiology Volume: 36 ISSN: 1440-1681 ISO Abbreviation: Clin. Exp. Pharmacol. Physiol. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-08-13 Completed Date: 2009-11-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0425076 Medline TA: Clin Exp Pharmacol Physiol Country: Australia |
Other Details:
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Languages: eng Pagination: 487-94 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Carcinoma, Non-Small-Cell Lung / genetics, metabolism, pathology* Cell Line, Tumor Cell Respiration / drug effects Enzyme Activation / drug effects Gene Expression Regulation, Neoplastic / drug effects Humans JNK Mitogen-Activated Protein Kinases / metabolism Lung Neoplasms / genetics, metabolism, pathology* Membrane Glycoproteins / genetics, metabolism Mitochondria / drug effects*, metabolism, physiology NADPH Oxidase / genetics, metabolism Protein Kinase Inhibitors / pharmacology Quinazolines / pharmacology* Reactive Oxygen Species / metabolism* Signal Transduction / drug effects |
| Chemical | |
Reg. No./Substance:
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0/CYBB protein, human; 0/Membrane Glycoproteins; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/Reactive Oxygen Species; 0/erlotinib; EC 1.6.3.1/NADPH Oxidase; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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