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研究生:江柏政
研究生(外文):Po-Cheng Chiang
論文名稱:珊瑚萃取物中的類前列腺素在人類肝癌細胞的作用研究
論文名稱(外文):Investigation of the Anticancer Mechanism of Marine Prostanoid-Like Clavulones, Derived from Clavularia viridis, in Human Hepatocellular Carcinoma Hep3B Cells
指導教授:顧記華顧記華引用關係
指導教授(外文):Jih-Hwa Guh
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:72
中文關鍵詞:類前列腺素肝癌內質網迫力細胞凋亡
外文關鍵詞:ER stresshepatomaprostanoidsapoptosis
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在本篇的論文中,我們對許多由天然物所分離出來的化合物做抗癌活性的篩選。在一連串的藥物篩選過程中,我們使用sulforhodamine B (SRB) assay發現珊瑚類前列腺素對於人類肝癌細胞株Hep 3B的增生有很好的抑制活性。珊瑚類前列腺素是一批從海洋珊瑚所萃取、純化出來的純化合物,結構與前列腺素非常類似。因為這一系列化合物的結構與前列腺素非常相似,所以在SRB assay的篩選過程中,我們將珊瑚類前列腺素與十一種前列腺素放在一起做比較,比較其抑制人類肝癌細胞Hep 3B生長的活性,結果發現,與各種前列腺素比較起來,珊瑚類前列腺素很明顯的有較強的活性,其中Bromovulone Ⅲ、Chlorovulone Ⅱ以及Chlorovulone Ⅲ展現了較好的活性,他們的GI50分別為0.55 µM、1.73 µM以及0.83 µM。我們利用Hoechst33342做螢光染色,證實Bromovulone Ⅲ確實能引起Hep 3B細胞產生DNA濃縮凝聚的現象,電子顯微鏡下的觀察,也發現Bromovulone Ⅲ能造成凋亡小體的形成;利用流式細胞儀來觀測細胞週期(cell cycle)的變化,結果顯示Bromovulone Ⅲ在作用48小時的情況下,也能明顯的引起Hep 3B細胞subG1期增加,這些結果都顯示Bromovulone Ⅲ會引起Hep 3B的細胞凋亡作用。接下來,我們利用西方點墨法來探討Bcl-2 家族蛋白以及caspase在Bromovulone Ⅲ作用下的表現。結果顯示,幾乎所有的Bcl-2 家族蛋白在Bromovulone Ⅲ的作用下都沒有明顯的變化,其中唯一有明顯變化的是Mcl-1。Mcl-1的表現與Bromovulone Ⅲ的濃度明顯呈現正向的關係。另一方面,caspase的作用情形在Bromovulone Ⅲ作用下的表現也有別於一般的細胞凋亡途逕。Caspase-3、caspase-6、caspase-8跟caspase-9在Bromovulone Ⅲ的作用下並沒有明顯被活化的跡象,而XIAP的表現則是隨著Bromovulone Ⅲ的作用時間增加而增加。至於m-calapin、caspase-7與caspase-12在Bromovulone Ⅲ作用下,明顯有被活化的情形。特別值得注意的是,Bromovulone Ⅲ會顯著的引起轉錄因子GADD153/CHOP的表現增加,而上述中的caspase-12與GADD153/CHOP都是內質網(endothelium reticulum)受到外在迫力(stress)時,所引發的特有反應。因此我們認為Bromovulone Ⅲ所引發的細胞凋亡機轉是經由內質網受到凋亡迫力(ER stress)而來的。此外,我們還有探討細胞內鈣離子濃度、細胞膜電位、粒線體的膜電位以及粒線體的體積在Bromovulone Ⅲ作用下的變化。結果發現,在Bromovulone Ⅲ的作用下,胞內鈣離子會明顯的上升,粒線體體積也會加大,細胞膜電位則會有過極化(hyperpolarization)的現象,電子顯微鏡下也觀察到,在Bromovulone Ⅲ作用下粒線體有充水脹大的情形,而內質網也有因受迫力而遺留下來的空泡。這些現象也都與內質網所引發的細胞凋亡有關。綜合上述研究結果推論,Bromovulone Ⅲ會有效的引發肝腫瘤細胞Hep 3B的凋亡作用,而這個凋亡作用可能是經由內質網受迫力,造成胞內鈣離子的上升,進而使m-calpain、caspase-7與caspase-12的活化,以及促進轉錄因子GADD153/CHOP的作用而造成的結果。
In this study, we have carried out an anticancer screening test in numerous components derived from several natural sources by sulforhodamine B (SRB) assay. We found that the prostanoid-like extract from Clavularia viridis displayed effective anti-proliferative and cytotoxic activities in human hepatocellular carcinoma Hep3B cells. Bromovulone Ⅲ, Chlorovulone Ⅱand Chlorovulone Ⅲ were the most effective compounds with 50% inhibition of growth (GI50) of 0.55 µM, 1.73 µM, and 0.83 µM, respectively. The anticancer effects of several prostaglandins (PG) were compared while only PGA1 and PGD2 showed modest effect by SRB assay, indicating the superiority of marine prostanoid-like extracts from Clavularia viridis. The prostanoid-induced DNA condensation was identified by Hoechst33342 staining technique in Hep3B cells. The data of electron microscopy also show the apoptotoc body formation. By using flow cytometry to detect the progression of cell cycle, we found that the population in subG1 phase dramatically increased in response to Bromovulone Ⅲ for 48 hours. All of these results reveal that Bromovulone Ⅲ is able to induce apoptotic cell death in Hep3B cells. By using Western Blotting analysis to investigate the expressions of Bcl-2 family of proteins and caspase cascades, the data showed that Mcl-1 but not the other Bcl-2 family proteins was up-regulated in response to Bromovulone Ⅲ stimulus. Furthermore, the caspase-related signaling pathways were also examined in this study. The data demonstrated that Bromovulone III had little influence on caspase-3, -6, -8 and -9, while significantly induced the expression of XIAP and activation of m-calapin, caspase-7 and -12 in Hep3B cells. It is worth noting that Bromovulone III could also induce the increase of expression of the transcription factor, GADD153/CHOP. Since caspase-12 and GADD153/CHOP are two biological markers activated in cells under endoplasmic reticulum (ER) stress, it is suggested that the apoptotic death in Hep3B cells induced by Bromovulone III is mediated through the ER stress. In this study, four other apoptotic signals were also examined, such as cytoplasmic calcium distribution, mitochondrial membrane potential and mass and plasma membrane potential. Besides, mitochondria swelling and ER-stress were detected by using electron microscopy methods. The data showed that Bromovulone Ⅲ could induce the increase of cytoplasmic calcium concentraction and mitochondrial mass, the depolarization of mitochondrial membrane potential and the hyperpolarization of plasma membrane potential. Taken together, it is suggested that Bromovulone Ⅲ can effectively induce the apoptotic death in Hep3B cells through ER stress-mediated activation of m-calapin, caspase-7 and -12, and the increase of protein expression of GADD153/CHOP.
縮寫表............................................................Ⅰ
中文摘要..........................................................Ⅲ
英文摘要..........................................................Ⅴ
背景.............................................................. 1
研究動機...................................................... 1
珊瑚類前列腺素................................................ 3
細胞凋亡與細胞壞死............................................ 3
細胞凋亡相關的訊息傳遞物質.................................... 3
實驗材料與方法....................................................10
(1) 實驗材料...................................................10
(2) 細胞培養...................................................10
(3) 細胞計數...................................................10
(4) 細胞存活率的測定...........................................11
(5) Hoechst33342染色法.........................................11
(6) 流式細胞儀測定細胞凋亡與細胞週期...........................11
(7) 流式細胞儀測定粒線體膜電位以及細胞膜電位...................12
(8) 粒線體體積.................................................12
(9) Fluo-3染色法...............................................13
(10) 西方墨點法................................................13
(11) 電子顯微鏡觀測............................................17
(12) 資料分析..................................................17
實驗結果..........................................................18
實驗討論..........................................................24
結論..............................................................36
圖表..............................................................37
參考文獻..........................................................63
參考文獻
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