Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20781
標題: 抑制肺癌藥物篩選平台之建立:有效藥物之鑑定暨其功能機轉探討
Establishment of anti-cancer drug screening platforms for lung cancer: The identification of effective drugs and functional mechanisms
作者: 賴怡樺
Lai, Yi-Hua
關鍵字: 肺癌;lung cancer;藥物篩選平台;HLJ1;血管新生因子;Src;drug screening platforms;HLJ1;VEGF;Src
出版社: 分子生物學研究所
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摘要: 
肺癌是國內外最常見的高死亡率癌症。由於癌細胞的轉移,造成病患預後狀況不
佳。癌轉移的過程中,癌細胞經由周邊血管或淋巴管移動至其他部位繼續分裂生
長,不僅會調控抑癌或致癌基因的表現,而且會分泌血管新生因子促進血管新生,加速癌轉移的發生。許多的藥理學家便嘗試著從保健草藥中尋求解答,以提供治療肺癌的新方向。然而,面對數以千萬計的保健藥材和未知的抗癌機轉,並沒有具專一性又具高效率的篩選藥物方法。根據實驗室先前的研究,我們已經發現 HLJ1 是一個新的抑癌基因且與非小細胞肺癌病人之預後存活率相關,可作為有潛力的藥物標靶。此外,血管內皮新生因子 (VEGF)與Src 會活化下游許多訊息傳遞路徑,導致血管新生與癌轉移,預期會是個有效的癌症治療標靶。在本研究中,我們將建立三個篩選藥物平台:第一與第二個平台為利用抑癌基因 (HLJ1)和血管新生因子 (VEGF) 啟動子之報導基因分析 (reporter gene assay) 模式來建立平台,進而篩選抑制肺癌細胞生長及調控血管新生之保健草藥並探討其作用機轉;第三個平台為發展電腦輔助藥物設計(CADD)平台來篩選有潛力的Src 抑制劑,這使我們容易於實驗室鑑定候選化合物,提高開發新藥物的可能性。利用報導基因之篩藥平台,我們從中草藥資料庫鑑定了數個草藥化合物可以增強HLJ1啟動子活性或減少VEGF 轉錄,進而抑制癌細胞的移動與侵襲。在這些草藥中,我們發現穿心蓮內酯 (andrographolide)確實可以顯著地促進HLJ1 蛋白質的表現並抑制體內外腫瘤生長,而且穿心蓮內酯也會經由活化JunB 來上調控HLJ1,進而調控AP-2α 結合至MMP-2 啟動子並抑制MMP-2 的表現。此外,由微陣列的分析結果指出穿心蓮內酯會影響細胞週期(cell cycle)、細胞凋亡(apoptosis)與細胞貼附相關訊息(adhesion-related biological signalling),包括絲裂原活化蛋白激酶(mitogen-activated protein kinase),貼附(focal adhesion)和緊密連接(tight junction)的途徑,這使得穿心蓮內酯具有抑制肺癌細胞侵入及生長的能力。另外,我們也發現毒毛旋花素(strophanthin)確實可以減少VEGF mRNA 的表現,並且有效地抑制肺癌細胞的侵襲、移動、非貼附性聚落形成、貼附性聚落形成的能力和活體內腫瘤的生長。而在血管生成(tube formation)試驗中顯示,毒毛旋花素也會抑制血管的生成。而且由即時定量聚合連鎖反應實驗證明,毒毛旋花素會抑制VEGF121 、VEGF165 以及VEGF189 的表現量。而第三個平台則是利用對接(docking)在SrcY418 的位置進行虛擬篩選,來尋找可以結合在Y418 位置的候選藥物。由實驗結果顯示有幾個化合物可以抑制Src 磷酸化,antihelminthic niclosamide 是其中一個化合物。實驗結果發現,niclosamide 確實會減少Src 磷酸化與肺癌細胞生存能力及誘導細胞凋亡,我們推測niclosamide 可能有臨床治療或預防肺癌進展的潛力。另外,我們進一步分析niclosamide 分子結構改變對於功效之影響。由實驗結果顯示在細胞生存能力中,niclosamide 其中一個衍生物(W3312)比niclosamide 更有效果。總之,niclosamide 可以抑制Src 活性與相關訊息途徑,並極具有臨床治療的潛力。綜合以上結果,我們建立了標的HLJ1 和VEGF 藥物篩選平台以及電腦輔助藥物設計平台,這些平台皆具有專一性並可快速地篩選新的抗癌化合物。利用這些平台,我們確定穿心蓮內酯、毒毛旋花素與niclosamide是很有潛力的新抗癌藥物,可以抑制非小細胞肺癌的腫瘤生長和侵襲。

High mortality lung cancer is the most frequent cause of cancer deaths worldwide,including Taiwan. Because of cancer cell metastasis, cancer patients have poor prognosis. The process of cancer metastasis, cancer cells via peripheral vascular or lymphatic move to other parts of the division and growth. The process not only regulate tumor suppressor gene or oncogene expression, cancer cells also secrete angiogenic factors to promote angiogenesis and accelerate cancer metastasis. A lot of pharmacologists try to find the answers from the traditional Chinese herb medicines. However, there is no specific and high-throughput way to screen thousands of these “health-care” herbs to unknown anti-cancer pathway. According to our previous studies, we have identified a novel suppressor gene (HLJ1) which might relate to patients’ survival rate in NSCLC and can be used as a potential drug target. The vascular endothelial angiogenic factors (VEGF) plays essential roles in the activation of many downstream signalling pathways, promotion of angiogenesis and cancer metastasis and is expected to be a potent target for cancer therapy. In this study, we establish three platforms of drug screening. The first and second platforms were the HLJ1 and VEGF-targeting drug-screening platforms which analyze the HLJ1 and VEGF promoter activities by reporter gene assay. Utilizing these platforms, we can screen herbal medicines with lung cancer cell growth inhibition and angiogenesis regulation and investigate their mechanisms. Third platform was computer-aided drug design (CADD) method, we used CADD to develope novel c-Src inhibitors. By CADD, it is easy to identify candidate compounds for biological validation, and increase the successful rate of new drug development. Utilizing drug screening platforms of reporter gene, we identified several herbal compounds from a Chinese herbal library with the capacity to enhance HLJ1 promoter activity or inhibit VEGF transcription and thereby inhibited cancer cell migration and invasion. Among the herbal drugs identified the andrographolide most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulated HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect genes that are dominantly involved in the cell cycle, apoptosis and adhesion-related biological signalling, including mitogen-activated protein kinase, focal adhesion and tight junction pathways, indicating the diverse effects of andrographolide on anticancer invasion and proliferation. In addition, we also found that strophanthin could decrease VEGF mRNA expression and inhibit cancer cell invasion, migration, anchorage-independent and -dependent growth and tumor growth. The tube formation assay was revealed that strophanthin can suppress angiogenesis. Furthermore, the expression of VEGF121, VEGF165 and VEGF189 of VEGF isoforms were repressed by strophanthin. The third platform, computational virtual screening of Src inhibitor by docking on Y418 site, is performed to find the candidate drugs which could bind on Src Y418 site. The results showed that several compounds can suppress Src phosphorylation, especially antihelminthic niclosamide. We demonstrated that niclosamide could reduce src phorsphorylation and lung cancer cell viability, and induce apoptosis, suggesting that niclosamide may have the potential for the clinical treatment or prevention of lung cancer progression in humans. Moreover, we also analyzed the effect of structural changes in the niclosamide molecule on its ability. The result showed that one of the niclosamide derivatives (W3312) was more effective than niclosamide in cell viability. In summary, niclosamide can suppress Src activity and related signaling pathway and make great potential for the clinical treatment. In conclusion, the HLJ1-targeting, VEGF-targeting drug-screening platforms and CADD are useful for screening of novel anticancer compounds. Using these platforms, we identified andrographolide, strophanthin and niclosamide potentially as promising new anticancer agents that could suppress tumor growth and invasion in NSCLC.
URI: http://hdl.handle.net/11455/20781
其他識別: U0005-2208201307224400
Appears in Collections:分子生物學研究所

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