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研究生:黃麗敏
研究生(外文):Li-Min Huang
論文名稱:爵床素A之抗肝癌作用機轉
論文名稱(外文):The mechanism of anti-hepatocellular carcinoma by Justicidin A
指導教授:黃玲惠翁舷誌
指導教授(外文):Lynn L.H. HuangShen-Jeu Won
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物科技研究所碩博士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:74
中文關鍵詞:爵床素A
外文關鍵詞:Justicidin A
相關次數:
  • 被引用被引用:2
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  • 收藏至我的研究室書目清單書目收藏:1
在我們的研究中發現,從爵床(J. procumbens)全草分離出來的一種已知成分爵床素A (justicidin A; JA)對人類肝癌細胞Hep 3B及Hep G2有細胞毒殺作用。在6天處理爵床素A的50%抑制影響劑量分別為Hep 3B是0.038 mM,Hep G2是0.078 mM,human peripheral blood mononuclear cells (PBMC)是23 mM以及Chang liver cells為0.949 mM。隨著爵床素A處理的時間及劑量增加,可以觀察到phosphatidylserine從細胞膜內轉至外面、Sub-G1時期的DNA含量以及DNA片段的形成。同樣地,爵床素A誘導的caspase-8, caspase-9及caspase-3活性也隨處理時間及劑量而變化。JA誘導細胞DNA片段的形成會被一種抑制所有caspases的抑制劑Z-VAD所抑制,這說明爵床素A誘導腫瘤細胞的細胞凋亡可能跟一連串的caspase活化有關。而cyclohexamide也會降低爵床素A引發的DNA片段形成,這些結果說明了爵床素A誘導人類肝癌細胞死亡是典型的細胞凋亡。以流式細胞儀及共軛聚焦顯微鏡分析看到爵床素A導致人類肝癌細胞的粒線體膜電位喪失。隨著爵床素A處理的時間及劑量增加Cytochrome c和Smac/DIABLO從粒線體釋放到細胞質,使得細胞內XIAP的含量降低、caspase-9及caspase-3活化、PARP及DFF45的裂解。更進一步發現爵床素A誘導Hep 3B的粒線體膜電位喪失受到Bid及Bax調控,但JA不影響Bcl-2和Bcl-XL。蛋白質之表現總而言之,我們的研究推測JA誘導肝癌細胞的細胞凋亡經caspase-8活化,促使粒線體上較早時期發生的Bid及Bax累積,導致粒線體膜電位喪失、Cytochrome c和Smac/DIABLO從粒線體釋放到細胞質、一連串下游的caspases活化及細胞核內的DNA片段形成。
Justicidin-A (JA), a natural antitumor agent isolated from Justicia Procumbens, inhibited the proliferations of both human Hepatocellular carcinoma Hep 3B and Hep G2 cells. Fifty percents of effective dose on day 6 of exposure to JA was 0.038 mM, 0.078 mM, 23mM, and 0.949 mM for Hep 3B, Hep G2, human peripheral blood mononuclear cells and Chang liver cells, respectively. The leakage of phosphatidylserine from the inner membrane to the outer layer of the plasma membrane, Sub-G1 DNA, and fragmentation of DNA were observed in a time- and dose-dependent manner on JA-treated cells. Treatment with JA also induced the activities of caspase-8, caspase-9 and caspase-3 in a time- and dose-dependent fashion. The apoptotic hallmark of DNA fragmentation events were inhibited by Z-VAD, a pan caspase inhibitor, indicating apoptosis of tumor cells induced by JA might depend on caspases cascade. Cyclosporin A and cyclohexamide also suppressed DNA fragmentation in JA-treated cells. Treatment with JA led to the loss of the mitochondrial membrane potential (Dym) by flow cytometry and confocal microscopy. The JA-treated cells caused the releases of Smac/DIABLO and cytochrome c from mitochondria to the cytosol in a time- and dose-dependent manner which were corresponding to the decreases the levels of XIAP and activations of caspase-9 and caspase-3, and decreases of DFF45 and cleavages of PARP. Furthermore, JA-induced the losses of Dym in human hepatocellular carcinoma cells were due to the translocations of Bid and Bax proteins from cytosol to the mitochondria, but not due to the decreases of the endogenous proteins Bcl-2 and Bcl-XL. Taken together, our findings suggest that JA induced human hepatocellular carcinoma cell apoptosis via the activations of caspase-8, which trigger the early events of accumulations of Bid and Bax proteins in mitochondria that lead to the losses of Dym, releases of Smac/DIABLO and cytochrome c to the cytosol, activations of downstream caspase cascades and nuclear DNA fragmentations.
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