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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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SUMMARY



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.



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 gp91phox expression and superoxide anion ( ) generation, suggesting that erlotinib induced ROS production in A549 cells from both mitochondrial and NADPH oxidase sources.



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.



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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Keywords: A549 cells; apoptosis; c-Jun N-terminal kinase (JNK); erlotinib; reactive oxygen species

Document Type: Research Article

Publication date: May 1, 2009

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