https://scholars.lib.ntu.edu.tw/handle/123456789/434936
標題: | Gefitinib-induced epidermal growth factor receptor-independent keratinocyte apoptosis is mediated by the JNK activation pathway | 作者: | Lu P.-H. Kuo T.-C. Chang K.-C. Chang C.-H. CHIA-YU CHU |
公開日期: | 2011 | 卷: | 164 | 期: | 1 | 起(迄)頁: | 38-46 | 來源出版物: | British Journal of Dermatology | 摘要: | Background Gefitinib (ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with a significant antitumour effect on various cancers. Skin toxicity induced by gefitinib is common, and has been shown to be related to the inhibition of EGFR signalling pathways. However, other mechanisms may be involved in gefitinib-induced skin toxicity. Objectives To study the possible EGFR-independent mechanisms of gefitinib-induced skin toxicity. Methods The human immortalized keratinocyte cell line HaCaT and human lung adenocarcinoma cell lines (A549 and PC9) were treated with different concentrations of gefitinib for 24, 48 and 72 h. Cell viability was measured by MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] after EGFR gene silencing. The signalling pathways were investigated by immunoblot analysis. Keratinocyte apoptosis was evaluated by nuclear condensation and flow cytometric analysis. Results Gefitinib maintained its cytotoxicity to HaCaT cells after EGFR gene silencing, indicating that an EGFR-independent mechanism exists. Increased phosphorylation of p38 mitogen-activated protein kinase and JNK by gefitinib was observed in a dose-dependent manner in HaCaT cells. The JNK inhibitor, SP600125, attenuated the gefitinib-induced cytotoxicity and apoptosis of HaCaT cells. Immunohistochemical examination of patient specimens showed an increased expression of phosphorylated JNK in lesional epidermis compared with nonlesional epidermis. Conclusions Gefitinib can induce keratinocyte apoptosis through an EGFR-independent JNK activation pathway. ? 2010 British Association of Dermatologists. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-78650431484&doi=10.1111%2fj.1365-2133.2010.10038.x&partnerID=40&md5=594b9fd5471f0e00e6893df16cab1ad3 https://scholars.lib.ntu.edu.tw/handle/123456789/434936 |
ISSN: | 0007-0963 | DOI: | 10.1111/j.1365-2133.2010.10038.x | SDG/關鍵字: | anthra[1,9 cd]pyrazol 6(2h) one; epidermal growth factor receptor; gefitinib; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase p38; stress activated protein kinase; apoptosis; article; cell viability; drug cytotoxicity; enzyme activation; enzyme phosphorylation; epidermis; flow cytometry; gene silencing; human; human cell; immunoblotting; immunohistochemistry; in vitro study; keratinocyte; lung adenocarcinoma; priority journal; signal transduction; skin toxicity; Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Flow Cytometry; Humans; Immunoblotting; Keratinocytes; Lung Neoplasms; Quinazolines; Receptor, Epidermal Growth Factor; Signal Transduction |
顯示於: | 醫學系 |
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