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系統識別號 U0026-0812200913372382
論文名稱(中文) 游離輻射合併三氧化二砷誘發U-118細胞自體吞噬之機制探討
論文名稱(英文) Study on the mechanisms of irradiation enhanced autophagic effect in U118 cells treated with arsenic trioxide
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 95
學期 2
出版年 96
研究生(中文) 邱惠雯
研究生(英文) Hui-Wen Chiu
學號 s7694107
學位類別 碩士
語文別 中文
論文頁數 80頁
口試委員 口試委員-何聖佑
召集委員-何元順
口試委員-潘敏雄
指導教授-王應然
中文關鍵字 三氧化二砷  放射線治療  惡性神經膠質瘤癌細胞株U118  自體吞噬 
英文關鍵字 Arsenic trioxide  Autophagy  Radiotherapy  U118 malignant glioma cell 
學科別分類
中文摘要 神經膠質瘤在成人中是最常見的惡性中樞神經系統的疾病,但是預後不佳。惡性神經膠質瘤最常使用的治療方法是放射線治療(IR)。但是放射線治療通常只能增加病人幾個月的存活率,並不能真正治療這種疾病。自體吞噬是在癌細胞處理放射線和三氧化二砷(ATO)時新發現的ㄧ種反應,但是其意義及機制到目前為止並不清楚。因此本實驗的目的主要是要了解放射線合併處理三氧化二砷對於惡性神經膠質瘤癌細胞株U118的影響,並且分析自體吞噬之機制。在細胞實驗中,利用trypan blue來計算細胞存活率。使用流式細胞儀分析細胞週期和藉由 annexin V-PE分析早期細胞凋亡。洋菜膠電泳分析DNA的片段化。DiOC6染劑分析粒線體膜電位。利用acridine orange染色觀察細胞自體吞噬的酸性小泡(AVO)發生。利用穿透式電子顯微鏡觀察U118細胞的超顯微結構。使用西方墨點法分析細胞自體吞噬反應和細胞凋亡調控相關之蛋白的改變。在動物實驗中,利用U118細胞株的腫瘤異種移殖模式來探討放射線合併三氧化二砷的治療效果。結果指出合併治療效果比單獨處理放射線及三氧化二砷效果較好。合併治療會降低細胞存活率、增加細胞週期的G2/M期的延遲及自體吞噬的百分比並會降低粒線體膜電位。合併治療會誘發產生自體吞噬而不是細胞凋亡。Hsp 70, p-ERK, p21, Bcl-2, Bcl-xl, p-p53,p-PTEN, p-GSK3β和LC3表現量增加而cycline A, cycline B, p-PI3K, p-Akt(Ser)和p-PDK1表現量減少。此外,前處理PI3K/Akt抑制劑LY294002更增加合併處理誘發的自體吞噬的百分比。然而,前處理MAPK抑制劑U0126更抑制合併處理誘發的自體吞噬的百分比。在動物實驗中,合併處理會抑制腫瘤的生長。此研究證明三氧化二砷能使對放射線治療具有抵抗性的U118細胞株更具治療效果。合併治療在U118細胞中所誘發的自體吞噬是經由抑制Akt/PKB的路徑和增加ERK/MAPK的路徑。
英文摘要 Gliomas are the most common malignancy of the central nervous system in adults, and the prognosis is extremely poor. Ionizing radiation (IR) is one of the standard therapeutic modalities for malignant gliomas. It improves the survival of the patients by several months, but does not cure the disease. Autophagy is a novel response of cancer cells to IR or arsenic trioxide (ATO), but its significance or mechanism remains largely elusive. The aim of this study is to understand the effect of IR combined with ATO for the treatment of U118 malignant glioma cells and analyze the molecular mechanisms of autophagy. In in vitro study, cell viability was detected by trypan blue. Cell cycle distribution and early apoptosis with annexin V-PE apoptosis detection kit was analyzed by flow cytometry. DNA fragmentation was detected by agarose gel electrophoresis. Mitochondrial membrane potentials assay was detected by DiOC6 dye. To observe the expressions of acidic vesicular organelle (AVO) which is characteristic of autophagy, cells were stained with acridine orange. Ultrastructure of U118 cells treated with IR, ATO and combined treatment was anayzed by electron microscopy. To analyze the expression of protein related to autophagy and apoptosis, western blotting was performed. In in vivo study, therapeutic efficacy of ATO and IR in U118 malignant glioma xenografts after treatment was assessed. The results indicated that the effect of combined treatment is more significant than irradiation or arsenic trioxide alone. Combined treatment reduced cells viability, increased cell cycle G2/M phase arrest, percentage of autophagy and reduced mitochondrial membrane potential (△Ψm). Particularly, combined treatment induced autophagic cell death but not apoptosis. Hsp 70, p-ERK, p21, Bcl-2, Bcl-xl, p-p53, p-PTEN, p-GSK3β and LC3 expression were increased. Cycline A, cycline B, p-PI3K, p-Akt (Ser) and p-PDK1 expression were decreased. In addition, pretreated with LY294002, a specific inhibitor of PI3K/Akt, further enhanced the combination-induced autophagy. Whereas pretreated with U0126, a specific inhibitor of ERK suppressed the combination-induced autophagy. In in vivo study, combined treatment inhibited tumor growth than treated alone. This study demonstrated that ATO increase the therapeutic efficacy of radiotherapy against U118 cells. One of the combined treatment induced autophagy in U118 cells were through inhibited Akt/PKB pathway and enhanced ERK/MAPK pathway.
論文目次 第一章、序論…………………………………………………………1
第二章、文獻回顧……………………………………………………2
第一節、人類惡性神經膠質瘤以及治療方式…………………2
第二節、放射線治療……………………………………………2
第三節、三氧化二砷(Arsenic trioxide)……………………5
第四節、放射治療合併化學治療……………………………………6
第五節、自體吞噬(Autophagy) ……………………………………9
第三章、研究目的……………………………………………………12
第四章、研究架構……………………………………………………13
第五章、研究材料與方法……………………………………………16
第一節、研究材料………………………………………………16
1.藥品試劑…………………………………………………16
2.常用儀器…………………………………………………17
3.常用溶液…………………………………………………18
第二節、研究方法………………………………………………19
ㄧ、人類惡性神經膠質細胞株(U118 cells)培養…………19
二、Trypan blue dye exclusion assay:細胞計數……21
三、Agarose gel electrophoresis………………………21
四、流式細胞儀(Flow cytometry)操作……………………22
五、螢光顯微鏡分析自體吞噬反應(Autophagy)現象……25
六、Western blot 步驟……………………………………25
七、電子顯微鏡……………………………………………29
八、動物實驗………………………………………………30
第三節、統計分析……………………………………………32
第六章、實驗結果…………………………………………………33
第一節、放射線和三氧化二砷對U118細胞之細胞毒性的
劑量及時間效應………………………………………33
第二節、探討U118 細胞之細胞週期變化及細胞凋亡現象……34
第三節、分析U118 細胞Autophagy的表現……………………35
第四節、細胞訊息傳遞路徑之相關蛋白表現…………………36
第五節、動物實驗- SCID mice xenograft 模式……………37
第七章、討論…………………………………………………………38
第八章、結論及建議…………………………………………………42
第九章、參考文獻……………………………………………………43

圖表……………………………………………………………………55

附錄……………………………………………………………………73
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