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標題: | HDAC抑制劑克服非小細胞肺癌之 gefitinib抗藥性之研究 HDAC inhibitor overcomes the gefitinib resistance in non-small-cell lung cancer |
作者: | Yun-Chieh Lin 林韵倢 |
指導教授: | 陳青周 |
關鍵字: | 非小細胞肺癌,HDAC抑制劑,Gefitinib, NSCLC,HDAC inhibitor,Gefitinib, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 非小細胞肺癌(NSCLC) 會表現過度活化之epidermal growth factor receptor (EGFR),促進腫瘤形成。EGFR-tyrosine kinase inhibitors (EGFR-TKIs) 如gefitinib與erlotinib,能抑制過度活化之EGFR,使癌細胞無法增生及轉移,用於治療EGFR突變之非小細胞肺癌;然而TKI 治療後如產生EGFR 之T790M 突變或MET 之gene amplification,造成治療失敗,即為secondary resistance,而克服secondary resistance是非小細胞肺癌治療之關鍵問題。
在許多腫瘤中HDAC 有過度表現,而降低抑癌基因之表現,因此HDAC 為癌症治療之熱門標的,HDAC 抑制劑可經由調節染色質組蛋白及non-histone protein之乙醯化,誘發癌細胞死亡、凋亡及細胞週期停滯而有抗癌效果。 本實驗篩選出HDAC 抑制劑compound D,可抑制NSCLC 之細胞生長及減少EGFR 與MET 之表現。Compound D 與gefitinib 合併使用,對gefitinib 具抗藥性細胞之生長有加成性抑制作用,亦抑制其下游AKT 及ERK 之活化,並促進癌細胞凋亡。在動物模式中,併用compound D 與gefitinib 可顯著抑制腫瘤生長。因此,gefitinib 併用HDAC 抑制劑可克服gefitinib 之抗藥性,對於產生secondary resistance之NSCLC 病患是具潛力之治療策略。 Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, which plays a pivotal role in cancer progression, is aberrantly overexpressed and abnormally activated in many cancers, such as non-small-cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib have been shown to improve overall survival and approved for the treatment of EGFR-mutant NSCLC. Recently, it has been signified that primary and secondary resistance to EGFR-TKIs limits their clinical significance. For instance, T790M mutation in EGFR or c-MET gene amplification makes up most cases of secondary resistance. Targeting mutant EGFR or c-MET could overcome TKI resistance in NSCLC. In our study, combination of gefitinib with HDAC inhibitor compound D overcomes TKI resistance in NSCLC cell lines. Compound D down-regulated EGFR and MET, and then disturbed the phosphorylation of AKT and ERK in NSCLC. Combination of compound D and gefitinib showed a synergistic antiproliferative effect through decreasing the activities of AKT and ERK and increasing apoptotic cell death. In addition, the compound D/gefitinib combination potentially inhibited in vivo tumor growth. Our data suggest that the compound D/gefitinib combination represents a promising strategy to overcome EGFR-TKI resistance in NSCLC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29252 |
全文授權: | 有償授權 |
顯示於系所單位: | 藥理學科所 |
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