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研究生: 曾嘉玲
Chia-Ling Tseng
論文名稱: 探討單獨使用新穎化學合成物Yao-ram-2-7或合併使用薑黃素對肝癌細胞的抑制並利用連接網路資料庫比對及證實Yao-ram-2-7之生理功能
To study anticancer effect of a novel compound Yao-ram-2-7 in the presence or absence of phytochemical curcumin on human hepatocellular carcinoma cells and to identify other biological function of Yao-ram-2-7 using Connectivity Map
指導教授: 蘇純立
Su, Chun-Li
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 126
中文關鍵詞: Yao-ram-2-7人類肝癌細胞細胞凋亡細胞自噬薑黃素SorafenibConnectivity Map
英文關鍵詞: Yao-ram-2-7, human hepatocellular carcinoma, apoptosis, autophagy, curcumin, Sorafenib, Connectivity Map
論文種類: 學術論文
相關次數: 點閱:242下載:6
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  • 肝癌是世界五大癌症之一,因不易早期發現及預後不佳,使得肝
    癌在癌症所致之死亡率高居不下。根據行政院衛生署統計,肝癌一直
    是國人癌症死因的大宗。治療肝癌方式,以手術和化學治療為主。在
    化學治療方面,藥效常局限於抗藥性的產生使藥效減低,因而促使研
    發更有效的新穎藥物。在本研究團隊自行合成一系列化合物中經
    MTT assay 篩選,發現 Yao-ram-2-7 具有抑制人類肝癌細胞(Hep 3B)
    生長的效用。在本研究中,Yao-ram-2-7 與臨床肝癌標靶用藥 Sorafenib
    在相同的實驗條件下比較,分別處理 Hep 3B 及人類臍靜脈內皮細胞
    (HUVEC)。發現 Yao-ram-2-7 與 Sorafenib 毒殺 Hep 3B 能力相當,
    處理 HUVEC 的安全性測試中,Yao-ram-2-7 毒性較 Sorafenib 弱,顯
    示 Yao-ram-2-7 可能對人體的副作用較小。利用 propidium iodide 染色分析細胞凋亡現象及以 acridine orange 染色分析細胞自噬現象,發現
    Yao-ram-2-7 誘發 Hep 3B 產生細胞凋亡及細胞自噬的比例隨時間和劑
    量增加而增加;利用西方墨點法也確定活化態 caspase 3 蛋白及 LC3-II
    蛋白的表現增加,證實 Yao-ram-2-7 可誘發 Hep 3B 產生細胞凋亡及
    細胞自噬。細胞凋亡實驗結果顯示,相較於 Sorafenib 在高劑量下才
    具有毒殺癌細胞能力,Yao-ram-2-7 在較低劑量下即有效果;細胞自
    噬實驗發現,Yao-ram-2-7 比 Sorafenib 在較低劑量下即可引發細胞產生自噬現象。因營養素可能具有輔助藥物效用,因此本研究也探討具
    有抗癌功用的天然植化素—薑黃素(Curcumin)與 Yao-ram-2-7 或
    Sorafenib 合併使用下,是否對抑制 Hep 3B 細胞生長有更好的效果。
    MTT assay 實驗結果發現 Hep 3B 在 Yao-ram-2-7 與薑黃素同時處理後,抑制細胞生長效果比單獨處理更佳,具有加乘效應;分析細胞週期的
    變化,發現合併使用薑黃素有使 G2/M 期增加的趨勢,使癌細胞分裂
    減少。但在肝癌標靶藥物 Sorafenib 與薑黃素合併使用則發現產生拮
    抗,因此建議臨床使用 Sorafenib 治療的患者不可食用含有薑黃素的
    食物及膳食補充品。另外,本研究透過「連接網路資料庫(Connectivity
    Map;CMAP)」比對,發現 Yao-ram-2-7 可能與 GSK-3 抑制劑
    AR-A014418 作用相似。實驗結果證實 AR-A014418 如 Yao-ram-2-7
    皆可誘發 Hep 3B 產生細胞自噬,Yao-ram-2-7 可抑制 phospho-GSK-3
    及總 GSK-3蛋白表現,顯示 Yao-ram-2-7 的生醫上的其它應用性。
    整體而言,本研究結果發現 Yao-ram-2-7 具有開發為抗癌用藥的潛力,
    提供肝癌病患治療上不同選擇;與薑黃素合併使用能增加藥物的敏感
    性,使化療藥物發揮更好的效果。

    Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. More than 75% cases of HCC occur in the Asia-Pacific region. High mortality of HCC is due to the difficulty in diagnosis and poor prognosis. Chemotherapy is a traditional choice for inoperable HCC, whereas drug resistant limits the therapeutic effect. Thus, there is an urgent need to develop new potential drugs for HCC. Our research group has synthesized a series of compounds for anti-cancer screening using MTT assay. Yao-ram-2-7 is one of them significantly inhibits the growth of HCC Hep 3B cells. Especially, Yao-ram-2-7 displays less cytotoxicity on normal human umbilical vein endothelial cells than the HCC targeted therapy Sorafenib, suggesting Yao-ram-2-7 is safer than Sorafenib. We further show that Yao-ram-2-7 induces apoptosis of Hep 3B cells in a time- and dose-related manner using propidium iodide staining followed by flow cytometry. Increase of cleavage-caspase 3 expression is observed using Western blotting. Yao-ram-2-7 also induces autophagy of Hep 3B cells characterized by the accumulation of acidic vesicular organelles by flow cytometry after staining the cells with acridine orange. Western blot analysis further observed the conversion of
    autophagy marker from LC3-I to LC3-II. Compared with Sorafenib, Yao-ram-2-7 induces apoptosis and autophagy at a relatively lower dosage for a shorter period of time. Recently, anticancer and chemopreventive effects of phytochemicals such as curcumin have been suggested. In the present study, combination of Yao-ram-2-7 with curcumin promotes growth inhibition of Hep 3B cells and produces an additivity effect. Cell cycle analysis suggests that the decrease in tumor cell proliferation is due to an increase of G2/M arrest. In contrast, addition of curcumin to Sorafenib displays an antagonism effect, suggesting that patients treated with Sorafenib should avoid food and supplements containing curcumin. In addition, we discover that a GSK-3 inhibitor AR-A014418 and Yao-ram-2-7 have similar biological functions since AR-A014418 alters gene expression of Hep 3B cells similarly to Yao-ram-2-7 by using a bioinformatics database Connectivity Map (CMAP). Western blot and flow cytometric analysis confirm that Yao-ram-2-7 behaves like AR-A014418, inducing autophagy and decreasing protein expression of phospho-GSK-3and total GSK-3 These data demonstrate that query gene expression profiles using CMAP is a useful shortcut to reveal molecular action of a small chemical compound. Taken together, our data suggest chemotherapeutic potential of Yao-ram-2-7 on HCC, and addition of curcumin further promots its chemosensitivity.

    第一章 緒論 1 第一節 肝癌 1 一、肝癌的對人類的威脅 1 二、肝癌的致病因子 1 三、肝癌的治療 2 第二節 薑黃素 7 一、薑黃素的背景 7 二、薑黃素與癌症的關係 8 第三節 計畫性細胞死亡 10 一、細胞凋亡 10 二、細胞自噬 16 第四節 細胞週期的意義 21 第五節 新穎化合物 Yao-ram-2-7 23 第六節 連結網路資料庫及 L1000 25 第二章 研究目的 27 第三章 材料與方法 29 第一節 儀器與實驗耗材 29 第二節 藥品與試劑 32 第三節 實驗方法 35 一、細胞培養 35 二、化合物的配製 38 三、細胞毒殺試驗 39 四、細胞週期分析 40 五、檢測細胞自噬比例 42 六、西方墨點法 43 第四章 結果 50 第一節 Yao-ram-2-7 可抑制癌細胞 Hep 3B 的生長,但對人類正 常臍靜脈內皮細胞 HUVEC 傷害較低 50 第二節 Yao-ram-2-7 能誘發 Hep 3B 細胞產生細胞凋亡 55 第三節 Yao-ram-2-7 能誘發 Hep 3B 細胞產生細胞自噬 61 第四節 薑黃素與 Yao-ram-2-7 合併使用對肝癌細胞的影響 64 第五節 薑黃素與 Sorafenib 合併使用對肝癌細胞的影響 73 第六節 驗證連接網路資料庫比對結果 81 第五章 討論 92 第六章 結論 100 第七章 參考文獻 101 附錄 118 Fig. 1 Yao-ram-2-7 is the one of 136 compounds exhibiting anticancer ability. 24 Fig. 2 Effect of Yao-ram-2-7 or Sorafenib on Hep 3B cell viability determined by MTT assay. 52 Fig. 3 Effect of Yao-ram-2-7 or Sorafenib on HUVEC cell viability determined by MTT assay. 53 Fig. 4 Yao-ram-2-7 induced apoptosis of Hep 3B cells in a dose- and time-related manner. 57 Fig. 5 Sorafenib induced apoptosis on Hep 3B cells in a dose- and time-related manner. 59 Fig. 6 Effect of Yao-ram-2-7 on autophagy of Hep 3B cells. 62 Fig. 7 Effect of Sorafenib on autophagy of HCC Hep 3B cells. 63 Fig. 8 Effect of Yao-ram-2-7 with or without curcumin on Hep 3B cell viability determined by MTT assay and the interaction of Yao-ram-2-7 and curcumin determined by the value of q. 68 Fig. 9 The effect of curcumin on Yao-ram-2-7-induced apoptosis. 69 Fig. 10 The change of caspase 3 protein expression in Yao-ram-2-7-treated Hep 3B cells in the presence and absence of curcumin. 71 Fig. 11 The change of LC3 protein expression in Yao-ram-2-7-treated Hep 3B cells in the presence or absence of curcumin. 72 Fig. 12 Effect of Sorafenib with or without curcumin on Hep 3B cell viability determined by MTT assay and the interaction of Sorafenib and curcumin determined by the value of q. 76 Fig. 13 The effect of curcumin on Sorafenib-induced apoptosis. 77 Fig. 14 The change of caspase 3 protein expression in Sorafenib-treated Hep 3B cells in the presence and absence of curcumin. 79 Fig. 15 The change of LC3 protein expression in Sorafenib-treated Hep 3B cells in the presence and absence of curcumin. 80 Fig. 16 Effect of Yao-ram-2-7 or AR-A014418 on Hep 3B cell viability determined by MTT assay. 84 Fig. 17 Effect of AR-A014418 on apoptosis of Hep 3B cells. 85 Fig. 18 The change of caspase 3 protein expression in AR-A014418-treated Hep 3B cell. 87 Fig. 19 Effect of AR-A014418 on autophagy of Hep 3B cells. 88 Fig. 20 The change of LC3 protein expression in AR-A014418-treated Hep 3B cell 89 Fig. 21 The change of phospho-GSK-3α/β protein expression in Yao-ram-2-7-treared Hep 3B cell. 90 Fig. 22 The change of total GSK-3β protein expression in Yao-ram-2-7-treated Hep 3B cell. 91 Table 1 The IC 50 of Yao-ram-2-7 and anticancer drug Sorafenib. 54 Table 2 The percentage of cells at different phases of cell cycle in Fig.4. 58 Table 3 The percentage of cells at different phases of cell cycle in Fig.5 .60 Table 4 The percentages of cells at different phases of cell cycle in Fig. 9 and the value of q 70 Table 5 The percentages of cells at different phases of cell cycle in Fig. 13 and the value of q 78 Table 6 The percentage of cells at different phases of cell cycle in Fig. 17 86 Appendix Fig. 1 Chemical structure of Sorafenib. 118 Appendix Fig. 2 Molecular mechanisms of Sorafenib. 119 Appendix Fig. 3 Curcuma longa Plant and chemical structure of curcumin, an active ingredient of rhizome termeric. 120 Appendix Fig. 4 Curcumin significantly inhibited protein expression of Aurora-A. 121 Appendix Fig. 5 Curcumin enhanced chemosensitivity of human breast cancer cells to Ixabepilone (FDA approved drug for patients with breast cancer). 122 Appendix Fig. 6 The apoptosis pathway. 123 Appendix Fig. 7 The process of autophagy. 124 Appendix Fig. 8 The mammalian cell cycle. 125 Appendix Fig. 9 The chemical of AR-A014418. 126

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