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研究生:劉瑞剛
研究生(外文):Ray-Gung Liu
論文名稱:探討動物性類毛地黃素物質蟾蜍靈之抗癌效果
論文名稱(外文):Anti-Cancer Effects of Animal Digoxin-like Compound Bufalin
指導教授:魏正舒魏正舒引用關係
指導教授(外文):Jeng-Shu Wei
學位類別:碩士
校院名稱:長庚大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:70
中文關鍵詞:蟾蜍靈細胞凋亡細胞週期DNA片段化
外文關鍵詞:bufalinapoptosiscaspase-3SK-Hep-1Hep-G2K562Jurkat
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肝癌是最具抗化療且癒後情況很差的癌症,即使採用創新的治療方式,其回報率低且持續性反應短,用蟾蜍靈(一種從蟾蜍萃取得到的強心類固醇)處理肝癌細胞株SK-Hep-1和Hep-G2,依據MTT細胞存活實驗,分化不良型的Sk-Hep-1細胞其蟾蜍靈半致死劑量為0.02μΜ,用細胞流式分析儀分析細胞週期變化,SK-Hep-1經蟾蜍靈處理48小時後停滯在G2/M和S期。此項蟾蜍靈對肝癌細胞週期的影響與先前報告其在血癌細胞細胞週期的影響導致停滯在G2/M期有所不同。因為先前的報告不曾有提及用蟾蜍靈處理正常細胞所產生之細胞毒性,所以我們用人類白血球細胞及周邊血液單核球細胞當模型探討。我們發現0.1至0.001μΜ蟾蜍靈會促進SD大鼠肝細胞和人類血球細胞百分之十到十五的生長率;相反地蟾蜍靈抑制SK-Hep-1、Hep-G2肝癌細胞和K562、Jurkat血癌細胞生長。用蟾蜍靈處理SK-Hep-1細胞後證明可以導致凋亡小體形成、DNA片段化、細胞膜上PS外翻、caspase-3的活化。使用0.1μM 蟾蜍靈處理肝癌細胞SK-Hep-1兩天後,凋亡細胞族群從5%上升至20%,對不同種類的癌細胞經由細胞凋亡機制使細胞死亡,但是正常細胞卻沒有傷害,動物性類固醇有潛力無副作用地用於肝癌和血癌的治療。
Hepatocellular carcinoma is at the forefront of chemotherapeutic resistant cancer with poor prognosis. Even with innovative treatment regimes, response rates remain low and the duration of response is short. In this report, bufalin, a cardiotonic steroid from toad was used to treat human hapatoma cell lines, SK-Hep-1 and Hep-G2 cells. The IC50 of bufalin on poorly differentiated Sk-Hep-1 was 0.02μM while that on well differentiated Hep-G2 at 2μM according to MTT cell viability test. Cell cycle changes, measured by flow cytometry, became evident at 48 hr after treatment of SK-Hep-1 cells with bufalin and the cells were preferentially arrested in both G2/M and S phases. This effect of bufalin on the cell cycle of hepatoma cells is different from that of only G2/M arresting in leukemia cells as reported previously by the other groups. Since previous reports did not include normal cells for study of bufalin’s cytotoxicity, we therefore investigated in this report the bufalin effect on normal human white cells and human peripheral blood mononuclear cells (PBMC) as well. We have demonstrated clearly buflin promotes rat liver cells and human white cells growth slightly (10 to 15%) but dramatically decreased SK-Hep-1, Hep-G2, and two leukemia cell lines, namely K562 and Jurkat at dose and time dependent manners. Bufalin can effectively induce apoptosis of SK-Hep-1 as demonstrated by apoptotic body formation, DNA fragmentation and activation of caspase-3 in SK-Hep-1 cells. In addition, percentage of apoptotic cells increased from 5% of total cell population in the control group to 20% using 0.1μM of bufalin for two days. Since bufalin has no negative effect on normal cells, but it does exert significant effects on different cancer cell lines via apoptotic mechanism, thus this animal steroid may provide a potential use for hepatoma and leukemia therapy without toxic side effects.
指導教授推薦書…………………………………………………………………………………………………………
口試委員會審定書………………………………………………………………………………………………………
授權書……………………………………………………………………………………………………………………
誌謝……………………………………………………………………………………………………………………… i
中文摘要………………………………………………………………………………………………………………… ii
英文摘要………………………………………………………………………………………………………………… iii
目錄……………………………………………………………………………………………………………………… v
第一章 緒論 …………………………………………………………………………………………………………… 1
1.1 台灣地區肝癌死亡率簡介………………………………………………………………………………………… 1
1.2 強心配糖體之簡介………………………………………………………………………………………………… 2
1.3 蟾酥之簡介………………………………………………………………………………………………………… 3
1.3.1 有效成分………………………………………………………………………………………………………… 4
1.3.2 藥理作用………………………………………………………………………………………………………… 4
1.4 蟾蜍靈之簡介……………………………………………………………………………………………………… 7
1.5 細胞週期…………………………………………………………………………………………………………… 8
1.6 細胞凋亡的機轉…………………………………………………………………………………………………… 9
1.7 細胞內鈣離子濃度與細胞凋亡的可能關係……………………………………………………………………… 12
1.8 實驗目的與假說…………………………………………………………………………………………………… 13
第二章 材料與方法 …………………………………………………………………………………………………… 14
2.1實驗試劑 …………………………………………………………………………………………………………… 14
2.2 細胞株的培養……………………………………………………………………………………………………… 15
2.3 細胞存活率分析…………………………………………………………………………………………………… 17
2.4 細胞型態觀察……………………………………………………………………………………………………… 18
2.5 細胞週期分析……………………………………………………………………………………………………… 18
2.6 Jc-1染色分析……………………………………………………………………………………………………… 19
2.7 Caspase-3 活性分析 …………………………………………………………………………………………… 20
2.8 Annexin-v & PI 雙染色分析 ……………………………………………………………………………………… 21
2.10 DNA Ladder分析 ………………………………………………………………………………………………… 21
2.11 統計分析 ………………………………………………………………………………………………………… 21
第三章 實驗結果 ……………………………………………………………………………………………………… 23
3.1 蟾蜍毒對於人類肝癌SK-Hep-1細胞增殖影響…………………………………………………………………… 23
3.2 蟾蜍靈、華蟾蜍、靈華蟾蜍它靈對SK-Hep-1細胞增殖影響…………………………………………………… 23
3.3 蟾蜍靈對於SK-Hep-1、Hep-G2與SD大鼠肝臟細胞增影響…………………………………………………… 23
3.4 蟾蜍靈對於血癌細胞與人類血液細胞增殖影響………………………………………………………………… 24
3.5 蟾蜍靈對於SK-Hep-1細胞的細胞週期影響……………………………………………………………………… 24
3.6 蟾蜍靈對人類肝癌SK-Hep-1細胞外觀之影響…………………………………………………………………… 25
3.7 蟾蜍靈對於SK-Hep-1細胞的Sub-G1期之影響…………………………………………………………………… 25
3.8 蟾蜍靈導致SK-Hep-1細胞進行細胞凋亡………………………………………………………………………… 26
3.9 蟾蜍靈對於SK-Hep-1細胞粒線體膜電位的影響………………………………………………………………… 26
3.10 蟾蜍靈對SK-Hep-1細胞caspases酵素活性的影響 …………………………………………………………… 27
第四章 討論 ……………………………………………………………………………………………………………… 28
第五章 結論 ……………………………………………………………………………………………………………… 34
參考文獻………………………………………………………………………………………………………………… 35
附圖……………………………………………………………………………………………………………………… 50
圖A、台灣地區歷年癌症死亡趨勢圖 ………………………………………………………………………………… 50
圖B、 蟾蜍靈抑制Na+,K+-ATPase活性,造成細胞內鈣離子溶度上升 …………………………………………… 51
圖C、 Digoxin 、 digitoxin 、ouabian 、bufalin、cinobufagin、cinobufatalin之分子結構…………………… 52
圖D、 Apotosis的主要路徑圖………………………………………………………………………………………… 54
圖一、不同濃度對蟾蜍毒人類肝癌細胞生長的影響………………………………………………………………… 55
圖二、不同濃度蟾蜍靈、華蟾蜍靈、華蟾蜍它靈對人類肝癌細胞生長的影響…………………………………… 56
圖三、不同濃度蟾蜍靈對人類肝癌細胞Sk-Hep-1與SD大鼠肝臟細胞生長的影響………………………………… 57
圖四、不同濃度蟾蜍靈對人類肝癌細胞Hep-G2生長的影響………………………………………………………… 58
圖五、不同濃度蟾蜍靈對人類血癌細胞Jurcat、K562 與人類血液細胞WBC、PBMC生長的影響……………… 59
圖六、不同濃度蟾蜍靈處理人類肝癌細胞Sk-Hep-1的細胞週期變化……………………………………………… 60
圖七、不同時間以0.1μΜ 蟾蜍靈 處理人類肝癌細胞Sk-Hep-1的細胞週期變化 …………………………………… 61
圖八、不同濃度蟾蜍靈處理人類肝癌細胞Sk-Hep-1的細胞型態…………………………………………………… 62
圖九、不同濃度蟾蜍靈處理人類肝癌細胞Sk-Hep-1的sub-G1期變化……………………………………………… 63
圖十、不同時間以0.1μΜ 蟾蜍靈處理人Sk-Hep-1的sub-G1期變化………………………………………………… 64
圖十一、不同時間以0.1μΜ 蟾蜍靈處理人類肝癌細胞Sk-Hep-1後細胞凋亡的變化……………………………… 65
圖十二、不同濃度蟾蜍靈處理人類肝癌細胞Sk-Hep-1產生的DNA ladder………………………………………… 66
圖十三、不同時間以0.1μΜ 蟾蜍靈處理人類肝癌細胞Sk-Hep-1的粒線體膜電位變化…………………………… 67
圖十四、不同時間以0.1μΜ 蟾蜍靈處理人類肝癌細胞Sk-Hep-1的粒線體膜電位變化(螢光顯微鏡)………… 68
圖十五、不同濃度蟾蜍靈處理人類肝癌細胞Sk-Hep-1後caspase-3活性變化 …………………………………… 69
圖十六、不同時間以0.1μΜ 蟾蜍靈處理人類肝癌細胞Sk-Hep-1後caspase-3活性變化 ………………………… 70
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