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National Chung Hsing University Institutional Repository - NCHUIR > 生命科學院 > 生物醫學研究所 > 依資料類型分類 > 碩博士論文 >  篩選一系列標靶Src的化合物且可以有效抑制肺癌發展

Please use this identifier to cite or link to this item: http://nchuir.lib.nchu.edu.tw/handle/309270000/152676

標題: 篩選一系列標靶Src的化合物且可以有效抑制肺癌發展
Novel Src-targeted compounds screening to identify the candidates that can inhibit lung cancer progression
作者: 林思吟
Lin, Sih-Yin
Contributors: 陳健尉
Jeremy J.W. Chen
生物醫學研究所
關鍵字: 酪胺酸激酶;酪胺酸激酶抑制劑
NSCLC;Src;EGFR
日期: 2013
Issue Date: 2013-11-18 11:04:47 (UTC+8)
Publisher: 生物醫學研究所
摘要: Non-small-cell lung cancer (NSCLC) is the most common cause of cancer deaths. Src is a tyrosine kinase and has been found to involve in cancer progression. The purpose of this study is to identify the compounds that target Src to suppress lung cancer tumorigenesis and metastasis, as well as to investigate their underlying molecular mechanisms. We first screened the potential compounds from LOPAC (1,280 molecules) and NCI (40,000 molecules) compound libraries by molecular docking approach. Twenty-three candidate compounds were selected and subjected to evaluate their efficacy in suppressing Src activity and its downstream by Western blot. Furthermore, the in vitro cell function assays were performed to investigate the effects of the selected candidate compounds on lung cancer cell proliferation, migration, invasion, and colony formation. Then we examined the effect of candidate compounds on the tumor growth via the xenograft model. We found that two compounds, L4 from LOPAC and N4 from NCI, are efficient in reducing the activity of phosphor-Src in a dose-dependent manner, as well as in that of Src downstream substrates including STAT3 and FAK. Cytotoxic assays indicated that the IC50s of L4 in PC9, PC9IR, and A549 are 0.05 μM, 0.11μM, and 0.13 μM at 72 hrs, respectively; and that the IC50s of N4 in those cell lines are 0.036 μM, 0.054μM, and 0.053 μM, respectively. Furthermore, these two compounds can significantly suppress, cancer cell proliferation, migration, invasion, and colony formation in vitro, as well as turmor growth in vivo, no matter the cell is Iressa-sensitive (PC9) or –resistant (A549 and PC9IR). Although the combination therapy with Iressa showed more significantly cytotoxic effect than Iressa alone; nevertheless, the effect is majorly derived from compound L4 or N4. Our data suggest that the inhibitory effect of compounds L4 and N4 on lung cancer progression might be through suppressing the phosphorylation and expression of Src, STAT3, and FAK. These findings will help us to develop the anti-cancer drugs for lung cancer.
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