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系統識別號 U0007-2207201114081200
論文名稱(中文) 薑黃素及其結構類似物誘導HT-29人類大腸癌細胞計畫性死亡之相關研究
論文名稱(英文) Studies on apoptotic activities of curcumin and its analogs in HT-29 human colorectal carcinoma cell
校院名稱 臺北醫學大學
系所名稱(中) 生藥學研究所
系所名稱(英) Graduate Institute of Pharmacognosy
學年度 99
學期 2
出版年 100
研究生(中文) 楊婷尊
研究生(英文) Ting-Chun Yang
學號 M303098001
學位類別 碩士
語文別 中文
口試日期 2011-06-27
論文頁數 103頁
口試委員 委員-林耀輝
委員-梁有志
指導教授-侯文琪
中文關鍵字 HT-29  薑黃素  大腸癌  人類大腸癌細胞 
英文關鍵字 apoptosis  colon  HT-29  colorectal carcinoma 
學科別分類
中文摘要 薑黃素(curcumin)是植物薑黃(turmeric)內主要具活性的成分,包括抗發炎、抗氧化、抗癌症轉移、誘導癌細胞計畫性死亡等活性。本篇研究探討薑黃素及其二十四個結構類似物抑制HT-29人類大腸癌細胞株增生和誘導細胞計畫性死亡的相關機制,並希望能篩選出比薑黃素更具細胞毒性之結構類似物。經由細胞存活率測試(resazurin assay),發現結構上具有一個甲氧基和三個羥基的七號結構類似物具顯著毒性,且有濃度依存性、時間依存性的現象;同時也比薑黃素較具有顯著的毒性,於是進一步探討與細胞毒性相關的研究。為了解七號結構類似物與細胞凋亡的關聯性,觀察細胞凋亡具代表性的特徵,在濃度40 ?嵱下,以光學顯微鏡觀察24小時候的HT-29細胞,觀察到細胞凋亡時會有的細胞膜突泡(blebbing)現象;利用流式細胞儀觀察細胞外膜Annexin V的結合量隨著七號結構類似物濃度的增加而增加,顯示細胞膜內的磷脂質絲胺酸(Phosphatidylserine)外翻的情形。以Hoechst 33342的染色下,可以看到染色體濃縮(condensation)的現象;在20 ?嵱下處理24 小時,觀察到HT-29細胞的G0/G1細胞週期停滯,40 ?嵱下處理24小時觀察到HT-29細胞有sub G1產生的現象。根據以上觀察到細胞凋亡時會產生的特徵,於是進一步了解細胞凋亡時之訊息傳導途徑及相關的蛋白質表現量。結果顯示,七號結構類似物會誘導caspase 3的活化,進一步活化caspase 9和caspase 8;粒線體膜電位的下降;Bcl-xl和Bcl-2的蛋白質表現量下降。而加入抗氧化劑(N-acetylcysteine, NAC)抑制ROS產生,細胞存活率明顯上升。顯示七號結構類似物可能會引起人類大腸癌細胞產生活性氧族及氧化逆境而進一步誘導走向細胞凋亡的現象。
英文摘要 Curcumin is a main bioactive constituent in turmeric which is used as food additives or herbs in southeastern Asia and India for a long time. It has been reported to exhibit anti-inflammatory, antioxidant, anti-metastatic, and apoptotic activities. In this study, curcumin and its 24 different kinds of analogs were selected to evaluate anti- HT-29 human colorectal adenocarcinoma and possible mechanisms. According to results of cell viable screenings (resazurin assay), it was found that analog 7 showed much higher growth inhibitory activities against HT-29 cells than that of curcumin under 20 ?嵱 and was selected as a candidate for further experiments. It was found that analog 7 showed dose-dependent and time-dependent toxicity against HT-29 cells. Therefore, the possibilities between toxicity of analog No.7 toward HT-29 cells and induction of apoptosis were investigated. Several hall marks of apoptosis were examined as followings. The blebbing of HT-29 cell membrane was observed by light microscopy under 40 ?嵱 for 24 h treatments. The annexin-V was dose-dependently bound to outer membranes of treated-HT-29 cells observed by the flow cytometry, which meant that the phosphatidylserine was externalized from inner membranes to outer membranes; the DNA condensed phenomena of HT-29 cells were found after being treated with different concentrations of analog No.7 which was stained with Hoechst 33342 fluorescent dyes and observed under UV-light microscopy; the cell cycles of G0/G1 was arrested and sub-G1 was appeared in treated HT-29 cells which were showed that analog No.7 could induce apoptosis in HT-29 cells. To study the possible mechanisms of apoptosis induced by analog No.7, the related apoptotic proteins in the intrinsic pathway and the extrinsic pathway were detected either by activity assays or by the western blotting. It was found that activities of casapase 3, caspase 8, and caspase 9 were increased, and the protein expression of PARP, Bcl-2, and Bcl-xl were dose-dependently reduced, and the mitochondrial membrane potentials were also reduced observed by JC-1 stains. To clearly understand the roles of reactive oxygen species (ROS) in apoptosis during analog No.7 treatments, the N-acetylcysteine (NAC) was used to compare the cell viability. It was found that 10 mM NAC pretreatment could increase the cell viability of HT-29 cells after treated with different concentrations of analog No.7 compared to the drug-treated one. It was proposed that analog No.7 treatment could increase ROS in HT-29 cells and then to produce oxidative stresses which in turn to induce apoptosis through intrinsic and extrinsic pathways.
論文目次 目錄
目錄……………………………………………………………………….I
圖目錄…………………………………………………………………..VI
表目錄……………………………………………………………..……IX
中文摘要…………………………………………..……………………XI
Abstract………………………………………………………………...XII
縮寫表…………………………………………………..…………….XIV

第一章 緒論…………………………………………………………….1
第一節 前言……………………………………………………1
第二節 文獻回顧………………………………………………2
壹、 薑黃素 curcumin………………………………….2
一、 簡介…………………………………………...2
二、 活性………………………………………...…3
三、 細胞計畫性死亡………………………….…10
四、 結構衍生物……………………………….…22
貳、 大腸直腸癌………………………………………25
一、 前言………………………………………….25
二、 分子生物學………………………………….27
三、 症狀及診斷……………….…………………28
四、 病理特性及分期…………………………….28
五、 輔助治療…………………………………….29
第二章 研究方法………………………………………………………30
1. 實驗材料………………………………………………………30
一、 儀器………………………………………………………..30
二、 試驗與耗材………………………………………………..31
三、 抗體……………………………………………………......32
四、 細胞株……………………………………………………..33
2. 實驗方法………………………………………………………37
一、 癌細胞之存活率試驗 resazurin assay…………...………37
二、 形態學觀察……………………………………………......38
三、 細胞計畫性死亡特徵—Annexin V-PE 單染實驗..……..39
四、 細胞週期試驗—DNA 分析法……..………………..…...40
五、 蛋白質定量……………………………..……..……….….41
六、 西方墨漬及免疫染色法…………………….....………….42
七、 染色體濃染試驗—Hoechst 33342 分析法….…….….…44
八、 Caspase-3, 8 活化態蛋白質表現量分析…….…….….…44
九、 粒線體膜電位-JC-1分析法……………………………....45
十、 NAC觀察其ROS 影響細胞存活率實驗……….………46
第三章 結果
1. 薑黃素及其二十四個結構類似物對於HT-29人類大腸癌細胞之細胞毒性……………………………………………………47
2. 薑黃素結構類似物對於HT-29人類大腸癌細胞之細胞毒性研究………………………………………………………………49
3. 七號薑黃素結構類似物處理HT-29人類大腸癌細胞之顯微鏡觀察--染色體濃縮(condensation)觀察………………………..52
4. 七號薑黃素結構類似物處理HT-29人類大腸癌細胞之流式細胞儀分析---細胞膜內磷脂質外翻…………………………... 55
5. 七號薑黃素結構類似物處理HT-29人類大腸癌細胞之形態學的觀察…………………………………………………………58
6. 七號薑黃素結構類似物對於HT-29人類大腸癌細胞細胞週期的影響…………………………………………………………60
7. 薑黃素及結構類似物七號對於半胱胺酸、天冬胺酸酶3 (caspase 3)活性的影響………………………………………..64
8. 薑黃素及結構類似物七號對於半胱胺酸、天冬胺酸酶8 (caspase 8)活性的影響……………………………………......66
9. 七號薑黃素結構類似物誘導HT-29人類大腸癌細胞原半胱胺酸、天冬胺酸酶9 (pro-caspase 9蛋白質表現量的影響……68
10. 七號薑黃素結構類似物誘導HT-29人類大腸癌細胞之聚腺苷二磷酸核糖聚合酶PARP (Poly (ADP-ribose) polymerase) 蛋白質表現量的影響……………………………………………70
11. 七號薑黃素結構類似物誘導HT-29人類大腸癌細胞 cytochrome C蛋白質表現量的影響………………………….72
12. 七號薑黃素結構類似物對於人類大腸癌細胞(HT-29)粒線體上膜電位變化的情形…………………………………………74
13. 七號薑黃素結構類似物誘導HT-29人類大腸癌細胞 Bax, Bcl-2, Bcl-xl蛋白質表現量的影響…………………………..76
14. 七號薑黃素結構類似物對於HT-29人類大腸癌細胞加入ROS 抑制劑 (NAC)後,細胞存活率變化的情形…………………80
第四章 討論
一、 篩選誘導大腸癌細胞計畫性死亡之薑黃素結構類似
物……………………………………...………………82
二、 結構類似物七號於細胞凋亡特性……………..……..….84
三、 結構類似物七號於細胞週期的影響………………..…...85
四、 結構類似物七號誘導HT-29細胞進行計畫性死亡經由細胞內途徑與細胞外途徑……………………………………...86
五、 結構類似物七號對於ROS的影響………………………87
六、 不同濃度的七號結構類似物對於抗氧化的影響及探
討……………………………………………………...88
第五章 結論 ……………………………………….………………….89
第六章 參考資料………………………………….………………….. 90

圖目錄
附圖一、 薑黃素(curcumin (R=H))的結構…………………………….3
附圖二、 薑黃素(curcumin (R=H))的結構…………………………….5
附圖三、 薑黃素影響癌症生成的階段及相關因子……………………5
附圖四、 薑黃素調控的分子標的………………………………….….9
附圖五、 薑黃素對於細胞性死亡分子之調控…………….………….10
附圖六、 caspase 活化示意圖………………………………………15
附圖七 、 caspase 發生途徑圖………………………………………18
附圖八、 細胞外途徑…………………………………………………20
附圖九、 細胞內途徑…………………………………………………22
附圖十、 薑黃素可修飾的官能基……………………………………..23
附圖十一、 薑黃素在動物體內的代謝產物……………………..…..24

圖一、 薑黃素及其二十四個結構類似物在濃度20 ?嵱下作用於HT-29細胞株72小時後細胞存活情形……………….……48
圖二、 以40 ?嵱的薑黃素及七號結構類似物處理HT-29細胞株於不同時間 (0, 12, 18, 24, 48, 72)小時後,HT-29細胞株存活情形……………………………………………………….…….50
圖三、 同濃度(10, 20, 30, 40, 60, 80 ?嵱)的七號結構類似物處理HT-29細胞株於不同時間(0, 12, 18, 24, 72)小時後,HT-29細
胞株存活情形…………………………………….………….51
圖四、 同濃度(10, 20, 30, 40, 60, 80 ?嵱)的七號結構類似物處理HT-29
細胞株於不同時間(0, 12, 18, 24, 72)小時後,HT-29細胞株存
活情形……………………..……..…………………………..53
圖五、 以流式細胞儀分析不同濃度之薑黃素七號結構類似物 (10到
60 ?嵱)處理HT-29人類大腸癌細胞12小時候,利用Annexin V測定細胞膜內磷脂質外翻情形……………………………….56
圖六、 以顯微鏡觀察40 ?嵱之七號結構類似物處理HT-29人類大腸
癌細胞24小時所產生的細胞膜空泡突起之細胞型態變化...59
圖七、 七號薑黃素結構類似物在不同濃度(20, 30, 40 ?嵱)處理不同時間(0,12,24 h)中細胞週期的變化情形對於HT-29人類大腸癌細胞細胞週期的影響…………………………………………….61
圖八、 七號薑黃素結構類似物在不同濃度(20, 30, 40 ?嵱)的時間點36小時對於HT-29人類大腸癌細胞的caspase 3 活性影響。HT-29細胞於處理前三十分鐘加入20 ?嵱 caspase 3抑制劑同時進行比較…………………………………………..…………65
圖九、 七號薑黃素結構類似物在不同濃度(20, 30, 40 ?嵱)的時間點36小時對於HT-29人類大腸癌細胞的caspase 8 活性影響。HT-29細胞於處理前三十分鐘加入20 ?嵱 caspase 8抑制劑同時進行比較…..…………………………………….…………67
圖十、 七號薑黃素結構類似物對於HT-29人類大腸癌細胞在不同濃度(10, 20, 30, 40, 60 ?嵱)下處理24 小時,以西方墨漬法檢測其pro-caspase 9蛋白質表現變化情形………………………….69
圖十一、 七號薑黃素結構類似物對於HT-29人類大腸癌細胞在不同濃度(20?嵱, 30?嵱, 40 ?嵱)下處理36 小時,以西方墨漬法檢測PARP蛋白質表現變化情形………………………………….70
圖十二、 七號薑黃素結構類似物對於人類大腸癌細胞(HT-29)細胞週期在不同濃度(10, 20, 30, 40 ?嵱)的時間點36 h中以西方墨漬法觀察其PARP蛋白質活性變化情形…………………….73
圖十三、 七號薑黃素結構類似物對於HT-29人類大腸癌細胞細胞週期在不同濃度(10, 20, 30, 40 ?嵱)下處理12小時其粒線體膜電位的變化情形………………………………………………….76
圖十四、 七號薑黃素結構類似物對於HT-29人類大腸癌細胞在不同濃度(10, 20, 30, 40, 60 ?嵱)下處理24 小時,以西方墨漬法檢測其Bax, Bcl-2, Bcl-xl蛋白質表現變化情形…………………..78
圖十五、 添加10 mM NAC對於七號薑黃素結構類似物在不同濃度下(10, 20, 30, 40 ?嵱)處理HT-29人類大腸癌細胞24小時之存活率變化……………………………………..………………..81

表目錄
表一、 薑黃素對於細胞性死亡分子之調控…………………………..12
表二、 caspase 分類及切位…………………………………………..14
表三、 Caspase 的受質…………………………………………..……17
表四、最新衛生署公布主要死亡原因排名……………….…..………26
表五、國民健康局統計97年國人十大癌症發生………….…………26
表六、七號薑黃素結構類似物在不同濃度(20, 30, 40 ?嵱)處理HT-29人類大腸癌細胞12小時後細胞週期的變化………………………….62
表七、七號薑黃素結構類似物在不同濃度(20, 30, 40 ?嵱)處理HT-29人類大腸癌細胞24小時後細胞週期的變化………………………….63
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