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• W2130424871 abstract "Purpose/Objective(s)The epidermal growth factor receptor (EGFR) is an important molecular target in head and neck cancer (HNSCC) and is involved in the activation of pro-survival pathways. EGFR is up regulated in over 90% HNSCC tumors and is associated with poor clinical prognosis, and resistance to chemo-/radio-therapy. We propose that EGFR inhibition with an EGFR tyrosine kinase inhibitor, Erlotinib, induces cytotoxicity via metabolic oxidative stress in HNSCC.Materials/MethodsProtein expression was determined by western blot analysis, cell growth was quantitated by coulter counter, cell survival was measured with the clonogenic survival assay, total glutathione and percent oxidized glutathione were determined using the spectrophotometric recycling assay, cell cycle distribution was determined by PI staining and flow cytometry, and CDCFH2 oxidation was measured using flow cytometry.ResultsErlotinib (10 μM) inhibited activated EGFR (pEGFR), total EGFR, activated Akt (pAkt) and total Akt expression in FaDu, Cal-27, SCC-25 and SQ20B head and neck cancer cells. Additionally, Erlotinib inhibited cell growth in all cell lines by inducing a G1 block over a 72 h period. Erlotinib treatment also caused significant clonogenic cell killing in all cell lines which was accompanied by significant increases in parameters indicative of oxidative stress such as percent oxidized glutathione (%GSSG) and CDCFH2 oxidation. EGFR-induced cytotoxicity and oxidative stress were both inhibited by the antioxidants N-acetylcysteine (NAC) and catalase. The combination of erlotinib and ionizing radiation additionally increased cell killing and parameters indicative of oxidative stress and these effects were mitigated with NAC treatment.ConclusionsThese results support the hypothesis that oxidative stress is involved in the mechanism of Erlotinib-induced cytotoxicity. The data presented here suggest that therapeutic strategies that inhibit EGFR activation combined with manipulations that increase pro-oxidant production and inhibit hydroperoxide metabolism may preferentially kill head and neck tumor cells vs. normal cells via oxidative stress. (supported by R01CA133114, R01 CA100045, T32 CA078586, and the Doris Duke Foundation) Purpose/Objective(s)The epidermal growth factor receptor (EGFR) is an important molecular target in head and neck cancer (HNSCC) and is involved in the activation of pro-survival pathways. EGFR is up regulated in over 90% HNSCC tumors and is associated with poor clinical prognosis, and resistance to chemo-/radio-therapy. We propose that EGFR inhibition with an EGFR tyrosine kinase inhibitor, Erlotinib, induces cytotoxicity via metabolic oxidative stress in HNSCC. The epidermal growth factor receptor (EGFR) is an important molecular target in head and neck cancer (HNSCC) and is involved in the activation of pro-survival pathways. EGFR is up regulated in over 90% HNSCC tumors and is associated with poor clinical prognosis, and resistance to chemo-/radio-therapy. We propose that EGFR inhibition with an EGFR tyrosine kinase inhibitor, Erlotinib, induces cytotoxicity via metabolic oxidative stress in HNSCC. Materials/MethodsProtein expression was determined by western blot analysis, cell growth was quantitated by coulter counter, cell survival was measured with the clonogenic survival assay, total glutathione and percent oxidized glutathione were determined using the spectrophotometric recycling assay, cell cycle distribution was determined by PI staining and flow cytometry, and CDCFH2 oxidation was measured using flow cytometry. Protein expression was determined by western blot analysis, cell growth was quantitated by coulter counter, cell survival was measured with the clonogenic survival assay, total glutathione and percent oxidized glutathione were determined using the spectrophotometric recycling assay, cell cycle distribution was determined by PI staining and flow cytometry, and CDCFH2 oxidation was measured using flow cytometry. ResultsErlotinib (10 μM) inhibited activated EGFR (pEGFR), total EGFR, activated Akt (pAkt) and total Akt expression in FaDu, Cal-27, SCC-25 and SQ20B head and neck cancer cells. Additionally, Erlotinib inhibited cell growth in all cell lines by inducing a G1 block over a 72 h period. Erlotinib treatment also caused significant clonogenic cell killing in all cell lines which was accompanied by significant increases in parameters indicative of oxidative stress such as percent oxidized glutathione (%GSSG) and CDCFH2 oxidation. EGFR-induced cytotoxicity and oxidative stress were both inhibited by the antioxidants N-acetylcysteine (NAC) and catalase. The combination of erlotinib and ionizing radiation additionally increased cell killing and parameters indicative of oxidative stress and these effects were mitigated with NAC treatment. Erlotinib (10 μM) inhibited activated EGFR (pEGFR), total EGFR, activated Akt (pAkt) and total Akt expression in FaDu, Cal-27, SCC-25 and SQ20B head and neck cancer cells. Additionally, Erlotinib inhibited cell growth in all cell lines by inducing a G1 block over a 72 h period. Erlotinib treatment also caused significant clonogenic cell killing in all cell lines which was accompanied by significant increases in parameters indicative of oxidative stress such as percent oxidized glutathione (%GSSG) and CDCFH2 oxidation. EGFR-induced cytotoxicity and oxidative stress were both inhibited by the antioxidants N-acetylcysteine (NAC) and catalase. The combination of erlotinib and ionizing radiation additionally increased cell killing and parameters indicative of oxidative stress and these effects were mitigated with NAC treatment. ConclusionsThese results support the hypothesis that oxidative stress is involved in the mechanism of Erlotinib-induced cytotoxicity. The data presented here suggest that therapeutic strategies that inhibit EGFR activation combined with manipulations that increase pro-oxidant production and inhibit hydroperoxide metabolism may preferentially kill head and neck tumor cells vs. normal cells via oxidative stress. (supported by R01CA133114, R01 CA100045, T32 CA078586, and the Doris Duke Foundation) These results support the hypothesis that oxidative stress is involved in the mechanism of Erlotinib-induced cytotoxicity. The data presented here suggest that therapeutic strategies that inhibit EGFR activation combined with manipulations that increase pro-oxidant production and inhibit hydroperoxide metabolism may preferentially kill head and neck tumor cells vs. normal cells via oxidative stress. (supported by R01CA133114, R01 CA100045, T32 CA078586, and the Doris Duke Foundation)" @default.
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• W2130424871 date "2009-11-01" @default.
• W2130424871 modified "2023-09-27" @default.
• W2130424871 title "The Role of Oxidative Stress in the Cytotoxic Effects of Erlotinib in Human Head and Neck Cancer Cells" @default.
• W2130424871 doi "https://doi.org/10.1016/j.ijrobp.2009.07.1292" @default.
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