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研究生: 范雅雯
Ya-Wen Fan
論文名稱: 探討薑黃素結合臨床抗癌藥物在人類膀胱癌細胞中之效果及機轉
The effect and molecular action of curcumin in FDA-approved clinical drug-treated human bladder cancer cells
指導教授: 蘇純立
Su, Chun-Li
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2014
畢業學年度: 102
語文別: 中文
論文頁數: 104
中文關鍵詞: 人類膀胱癌細胞薑黃素極光激酶細胞凋亡細胞自噬FDA核准臨床用藥
英文關鍵詞: Human bladder cancer cell, Curcumin, Aurora A, Apoptosis, Autophagy, FDA-approved anti-cancer drugs
論文種類: 學術論文
相關次數: 點閱:230下載:3
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  • 膀胱癌是泌尿系統中最常見的腫瘤疾病,可能與環境中砷暴露量較高而導致Aurora A過度表現有關。膀胱癌中發現Aurora A及表皮生長因子(EGF)有過度活化的情形,跟細胞增生有關。FDA核准的臨床藥物以Gemcitabine搭配Cisplatin/Carboplatin是目前傾向使用的化療藥物。希望將臨床藥物搭配薑黃素,藉由抑制Aurora A基因及相關蛋白表現,延緩癌細胞生長。以MTT assay決定各臨床藥物作用在膀胱癌T24細胞的濃度為0.05~0.1 μM Gemcitabine加0.5 μM Cisplatin/ 5 μM Carboplatin。結合薑黃素15 μM計算出CI值皆呈現協同作用。以流式細胞儀分析細胞週期,臨床用藥結合薑黃素增加代表細胞凋亡比例sub-G1 phase,增加代表可能跟抑制Aurora A相關G2/M phase停滯的比例,而且同時會引起細胞自噬作用。以西方墨點法發現薑黃素合併使用臨床藥物,抑制phospho-Aurora A、p62、Beclin-1、phospho-PI3K、phospho-p70s6k、Atg12-Atg5等蛋白表現,增加LC3-II、phospho-mTOR、phospho-AKT、phospho-MEK、phospho-ERK等蛋白表現。綜合以上結果,薑黃素合併臨床用藥能增加膀胱癌T24細胞毒殺效果及增加sub-G1期凋亡比例,增加化療敏感性,且抑制T24細胞Aurora A的活性,經由活化MEK/ERK路徑而促進自噬作用。

    Bladder cancer is the ninth most common cancer worldwide and the fourteenth most diagnosed malignancy in Taiwan (2013). Gemcitabine plus cisplatin (GC) treatment is prefered for nowadays treatment. For patients with impaired renal function, gemcitabine plus carboplatin (GCa) treatment is recommended. Overexpressions of Aurora A kinase and epidermal growth factor (EGF) were observed in bladder cancer cells. Our previously data demonstrate that curcumin significantly inhibited Aurora A gene expression, in part caused failure of various mitotic events and G2/M arrest of human bladder cancer cells. In this study, human bladder cancer T24 cells were treated with the existing chemotherapy (GC or GCa) in the presence and absence of curcumin. Addition of curcumin not only produced synergism using combination index analysis, but also raised the percentages of phases in sub-G1 (apoptosis rate) and G2/M using flow cytometry. Combinatio of cucurmin induced autophagy. Decreasing of phospho-Aurora A, p62, Beclin-1, phospho-PI3K, phospho-p70s6k, Atg12-Atg5 and increasing of LC3-II, phospho-mTOR, phospho-AKT, phospho-MEK, phospho-ERK were observed. Taken together, clinical drugs combined with curcumin not only inhibited activity of aurora a, but also promoted apoptosis and autophagy in T24 cells.

    第一章 緒論 1 第一節 膀胱癌 1 一、膀胱癌的發生 1 二、膀胱癌的臨床治療 2 第二節 薑黃素(Curcumin) 4 第三節 極光激酶(Aurora kinase) 6 第四節 計畫性細胞死亡(Programmed cell death,PCD) 8 一、細胞凋亡(Apoptosis) 8 二、細胞自噬(Autophagy) 11 第二章 研究目的 15 第三章 材料與方法 17 第一節 實驗藥品與試劑 17 第二節 實驗器材、耗材與實驗方法 20 一、細胞株繼代培養、解凍及保存 20 二、藥物配置 25 三、細胞存活率分析 27 四、細胞週期比例分析 28 五、細胞自噬比例分析 31 六、西方墨點法 33 七、Combination index計算方式 43 八、統計分析方法 43 第四章 結果 44 第一節 檢測FDA核准的臨床用藥合併使用後的效果 44 第二節 分析藥物合併使用後是否造成細胞週期改變 48 第三節 探討Curcumin合併使用FDA核准的臨床藥物是否透過抑制Aurora A路徑 52 第四節 調整Curcumin及FDA核准臨床用藥的濃度 55 第五節 分析藥物合併使用Curcumin後促T24細胞凋亡作用 61 第六節 藥物合併使用Curcumin後會引起T24細胞自噬作用 65 第七節 Curcumin合併使用FDA核准臨床用藥影響的路徑 69 第五章 討論 76 第六章 結論 81 第七章 參考文獻 82 圖次 Fig. 1 Percentage of inhibition of T24 cells in response to FDA-approved clinical drugs and Curcumin. 46 Fig. 2 Cytotoxicity of FDA-approved clinical drugs combined with Curcumin. 47 Fig. 3 The change of cell cycle distribution in response to FDA-approved clinical drugs in the presence and absence of Curcumin. 51 Fig. 4 Expressions of Aurora kinases in response to Curcumin combined with FDA-approved clinical drugs. 54 Fig. 5 Percentage of inhibition of T24 cells in response to FDA-approved clinical drugs and Curcumin. 58 Fig. 6 Combination index of T24 cells in response to FDA-approved clinical drugs and Curcumin. 60 Fig. 7 The change of cell cycle distribution in response to FDA-approved clinical drugs in the presence and absence of Curcumin. 63 Fig. 8 Curcumin 15 μM decreases activity both the pro-caspase 3and cleavaged-caspase 3. 64 Fig. 9 Effect of Curcumin combined with FDA-approved clinical drugs on autophagy of T24 cells. 67 Fig. 10 Curcumin induced increases in LC3-II and decreases in p62. 68 Fig. 11 Curcumin 15 μM downregulated activity of phospho-Aurora A . 71 Fig. 12 Curcumin 15 μM with FDA-approved clinical drugs or absence downregulated the expressions of Beclin-1. 72 Fig. 13 Curcumin 15 μM with FDA-approved clinical drugs or absence induced the activity of MEK/ERK pathway. 73 Fig. 14 Expression of Atg12-Atg5 and Atg5 with Curcumin combined with FDA-approved clinical drugs in T24 cells. 75   附錄 Appendix Fig. 1 Model. 104

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