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標題: 篩選分析在非小細胞肺癌內對Src激酶有效之化合物
Screening And Characterization of The Effective Compounds Targeting Src Kinase in Non-Small Cell Lung Cancer
作者: 張琇惠
Chang, Hsiu-Hui
Contributors: 陳健尉
生物醫學研究所
關鍵字: 酪胺酸激酶抑制劑;酵素結合免疫分析法
non-small cell lung cancer;tyrosine kinase inhibitor;ELISA
日期: 2013
Issue Date: 2013-11-18 11:04:51 (UTC+8)
Publisher: 生物醫學研究所
摘要: 肺癌是最惡性的疾病,導致了全球多人死亡。Src為致癌基因,在癌症的發展中扮演著重要的角色,在癌症治療上可能成為一個有效的標靶。因此,本研究主旨為確認在肺癌中標靶Src的有效化合物,並評估其治療的療效。使用Src pY419 ELISA做為藥物篩選平台以篩選超過500個植物有效成分的化合物藥庫,並利用西方墨點法分析Src及其下游蛋白的活性。利用細胞增生、移動、侵襲及聚落形成能力等實驗研究有效化合物對肺癌的影響,且印證在異殖腫瘤裸鼠模型。此研究中,透過ELISA方法,我們確認了五個有效化合物在A549肺癌細胞株中有能力抑制Src活性超過50 %。確定的化合物中,候選藥物1、候選藥物2及候選藥物3抑制Src Y419活性最為顯著,且其蛋白表現隨劑量上升而減少,亦可降低EGFR及STAT3的活性。為了研究這三個候選藥物的效果,使用這些化合物處理A549細胞24小時後,進一步分析細胞功能。結果顯示,這些化合物在體外試驗中能抑制A549的細胞增生、侵襲、移動及聚落形成能力,且在動物試驗中亦可降低腫瘤生長。在其他肺癌細胞株中,這些化合物都有著類似的效果。此外,我們還發現了這些化合物能誘發肺癌細胞死亡。我們的數據顯示了,Src pY419 ELISA藥物篩選平台在新型抗癌化合物篩選上是有效的。利用此平台,我們確認了候選藥物1、候選藥物2及候選藥物3可能能透過抑制Src、EGFR及STAT3的活性以抑制肺癌發展來做為潛在的抗癌藥物。需要進一步研究以評估它們在癌症患者上化療或標靶治療的應用,無論是單獨或聯合治療。
Lung cancer is the most malignant disease which makes lots of people dead worldwide. Src is an oncogene and plays an important role in cancer progression, as well as may be a useful target for cancer therapy. Therefore, this study aims to identify the effective compounds targeting Src in lung cancer and to evaluate their efficacy of treatment. Src pY419 ELISA was used as the drug-screening platform to screen compound library of more than 500 plant active ingredients. The Src expression, activity, and its downstream proteins were analyzed by Western blot. The effects of the active compounds on lung cancer were investigated by using cell proliferation, migration, invasion, and colony formation assay, as well as the tumor xenograft nude mouse model. In this study, by using the ELISA approach, we identified five active components with the capacity to inhibit the Src activity more than 50% in A549 lung cancer cell line. Among the compounds identified, the candidate drug 1, candidate drug 2 and candidate drug 3 could most significantly suppress the Src Y418 activity and protein expression in a dose-dependent manner, as well as reduce EGFR and STAT3 activity. In order to investigate the effect of these three candidate drugs, the A549 cells were treated with these compounds for 24 hour and then subjected to perform cell function analyses. The results showed that these compounds can inhibit A549 cell proliferation, invasion, migration, and colony formation in vitro, as well as reduce tumorigenesis in vivo. In other lung cancer cell types, these compounds have the similar effects. Furthermore, we also found that these compounds can induce program cell death of lung cancer cells. Our data suggest that Src pY419 ELISA drug-screening platform is useful for screening of novel anti-cancer compounds. By using this platform, we identified candidate drug 1, candidate drug 2 and candidate drug 3 as the potential anti-cancer agents which might inhibit lung cancer progression through suppressing Src, EGFR and STAT3 activity. Further investigation is required to evaluate their applications in chemotherapy or targeted therapy of cancer patients, either monotherapy or combination therapy.
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