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系統識別號 U0026-0812200910432300
論文名稱(中文) Formosanin C 抗大腸直腸癌之作用機轉
論文名稱(英文) The Anti-tumor Mechanism of Formosanin C in Human Colorectal Cancer Cells
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 91
學期 2
出版年 92
研究生(中文) 陳玲玲
研究生(英文) Ling-Ling Chen
電子信箱 ling2chen@hotmail.com
學號 s4690107
學位類別 碩士
語文別 中文
論文頁數 44頁
口試委員 指導教授-翁舷誌
口試委員-林忠男
口試委員-劉校生
指導教授-李政昌
中文關鍵字 生長抑制  細胞凋亡 
英文關鍵字 caspase  growth inhibition  apoptosis 
學科別分類
中文摘要 Formosanin C (PF-C)是從傳統中草藥植物Paris formosana Hayata純化出之天然成份,可誘發大腸直腸癌細胞株HT-29產生細胞凋亡(apoptosis)之反應。以PF-C處理HT-29細胞6天,其50%之抑制濃度(IC50)為1.04 mM,而以PF-C處理人類週邊單核細胞(PBMC)與人類臍靜脈內皮細胞(HUVEC),其IC50分別為24 mM與12.6 mM。以PF-C處理HT-29細胞後,細胞膜內面之磷脂絲胺酸(phosphatidylserine)翻轉至細胞外表面,且細胞週期sub-G1 之DNA含量增加,並觀察到DNA片段化(DNA fragmentation)之現象,這些結果顯示PF-C是透過細胞凋亡的過程抑制HT-29細胞生長。以西方墨點法(Western blot analysis)探討PF-C誘導細胞凋亡的分子機制,發現會造成caspase-2之活化、粒線體之Bax和Bak表現量增加,以及粒線體之Bcl-XL表現量減少。另外,以PF-C處理HT-29細胞後,會造成粒線體膜電位(ΔΨm)之喪失,cytochrome c 與 Smac/DIABLO由粒線體膜間區釋放至細胞質,XIAP蛋白質表現量減少並造成caspase-9與caspase-3之活化,進而切割活化DFF45,最後誘發DNA的斷裂。由流式細胞儀與共軛焦顯微鏡分析,發現PF-C引發細胞凋亡之作用與造成粒線體ΔΨm喪失之情形可被caspase-2之抑制劑Z-VDVAD-fmk、caspase-9之抑制劑Z-LEHD-fmk和cyclosporin A所回復。綜觀以上實驗結果推測,以PF-C處理大腸直腸癌細胞HT-29後,會造成caspase-2之活化、粒線體ΔΨm之喪失、cytochrome c 與 Smac/DIABLO由粒線體釋放至細胞質、XIAP蛋白質表現量減少,繼而活化下游分子,最終造成細胞凋亡。本篇研究結果針對PF-C作用分子機制之探討,有助於新藥之設計,以減緩大腸直腸癌疾病之進程並嘉惠病患。
英文摘要 The natural product of formosanin C (PF-C), isolated from Paris formosana Hayata, a traditional Chinese herbal remedy, induces strong apoptotic responses of human colorectal cancer cell HT29. The 50% inhibition concentration (IC50) of PF-C on HT29 cells was 1.04 mM as compared to normal human peripheral blood mononuclear cells (24 mM) or HUVEC (12.6 mM) at 6 days of post-treatment. The apoptotic process is demonstrated by the phenomena of phosphatidylserine exposure, magnifying of sub-G1 content, and DNA fragmentation. The molecular mechanism events of PF-C triggered apoptosis are associated with the activation of caspase-2, up expressions of mitochondrial Bax and Bak, and down expression of mitochondrial Bcl-XL. Furthermore, treatment with PF-C leads to the loss of mitochondrial membrane potential (ΔΨm), releases of cytochrome c and Smac/DIABLO from mitochondria to cytosol, decrease of XIAP protein and activations of caspase-9 and -3, and in turn to cleave PARP and DFF45, and then induces DNA fragmentation. The apoptosis and the loss ofΔΨm induced by PF-C are reversed by Z-VDVAD-fmk (caspase-2 inhibitor), Z-LEHD-fmk (caspase-9 inhibitor) and cyclosporin A using flow cytometry or confocal microscopy analysis. Thus, PF-C treatment of colorectal cancer cell HT29 causes activation of caspase-2, loss ofΔΨm and the down stream apoptotic events to lead the cell death. These results suggest that the molecular mechanism of PF-C may shed light on novel drugs design against carcinogenesis of human colorectal cancer progression.
論文目次 總目錄
中文摘要…………………………………………… II
英文摘要…………………………………………… III
圖表目錄…………………………………………… IV
縮寫對照表………………………………………… VI
誌謝………………………………………………… VIII
緒論………………………………………………… 1
材料與方法………………………………………… 13
結果………………………………………………… 28
討論………………………………………………… 37
參考文獻…………………………………………… 45
附圖表……………………………………………… 59
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