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系統識別號 U0007-2907201418004500
論文名稱(中文) PE092002 抑制胃癌細胞株生長之機制探討
論文名稱(英文) Mechanism Studies of PE092002 in Growth Inhibition of Gastric Cancer Cells
校院名稱 臺北醫學大學
系所名稱(中) 藥學系(碩博士班)
系所名稱(英) School of Pharmacy
學年度 102
學期 2
出版年 103
研究生(中文) 楊純慧
研究生(英文) Chun-Hui Yang
學號 M301101029
學位類別 碩士
語文別 中文
口試日期 2014-07-10
論文頁數 97頁
口試委員 指導教授-鄭幼文
委員-康照洲
委員-王惠珀
中文關鍵字 胃癌  抗分裂試劑  細胞凋亡  細胞自噬 
英文關鍵字 gastric cancer  antimitotic agent  apoptosis  autophagy 
學科別分類
中文摘要 胃癌的發生率與死亡率在全球癌症排名中占據重要的地位,於國際間相當盛行,且消耗相當大的醫療成本,但是在胃癌的治療方法上卻仍有許多的限制。近年來除了細胞凋亡被廣泛的應用於癌症治療之外,細胞自噬與癌症治療之間的研究亦越來越多,因此本研究將探討試驗藥物PE092002 (Hui-Po Wang, 2008),也會針對PE092002在細胞自噬中的抗癌潛力作探討。過去的研究指出,PE092002對於多種癌症細胞株的細胞存活率皆有顯著性的抑制生長效果,並且在異體移植 ( Xenograft model ) 的活體實驗中也能有效延緩腫瘤生長,但卻並未有任何與胃癌相關的研究。於是本次研究將探討 PE092002 對治療胃癌的功效及其可能機轉。實驗結果發現,處理 PE092002在濃度100 nM時開始顯著抑制胃腺癌細胞株AGS 以及胃癌細胞株 N87之細胞存活率,且在濃度30-50 nM 可以誘導細胞產生細胞週期G2/M時期之滯留效果,進而抑制細胞有絲分裂之進行。接著以Annexin V-FITC / PI 雙染的細胞凋亡試驗中發現,PE092002的處理可導致N87 細胞走向細胞凋亡,並在西方墨點法 ( western blot ) 中發現Bcl-2蛋白參與了PE092002導致細胞凋亡之調控。進一步地,以螢光物質monodansylcadaverine ( MDC ) 染自噬體囊泡 ( autophagosome )、Acrodine orange (AO)染在自噬溶酶體 ( autolysosome )中,並配合細胞轉染質體GFP-LC3蛋白的方式,觀察自噬體囊泡形成與變化,結果發現,兩株細胞皆在PE092002處理下有誘導細胞自噬的能力。並在加入細胞自噬抑制劑 Bafilomycin A1 之後,可反轉 PE092002 所造成的 AGS 細胞死亡傷害;並在西方墨點法中證明PE092002會調控 LC3-II 及 p62/SQSTM1 蛋白的表現,顯示PE092002的確造成胃癌細胞株細胞自噬。在PE092002調控的上游訊息傳遞路徑中,PE092002會抑制胃癌細胞中 mTOR/Akt 以及活化 MAPKs。並透過 ERK/JNK 參與調節Bcl-2蛋白表現,並誘導N87細胞凋亡;PE092002還會經由AKT/mTOR 和MAP kinases ERK/JNK 兩條路徑調控AGS細胞中LC3-II、p62及Bcl-2蛋白導致AGS細胞自噬性死亡。綜合本次研究結果顯示,PE092002可有效抑制胃癌細胞AGS和N87之細胞存活率,,並造成細胞週期G2/M期的滯留進而抑制細胞有絲分裂進行。並在能調控胃癌細胞中細胞自噬以及細胞凋亡的死亡,有開發為胃癌用藥之潛力。
英文摘要 Gastric cancer (GC) is one of the most common cancers and the leading cause of cancer-related death worldwide. However, the available options for GC treatment are limited. Over the past decades, most of anti-cancer drugs have been shown to induce apoptosis and cytotoxicity. Recently, numerous studies have focused on the relationship between autophagy and cancer therapy. Thus, autophagy is a prospective target for development of anti-cancer treatment. PE092002 (PE) is a novel piperazinedione compound (Hui-Po Wang, 2008). It has been proved that PE has great potential of anti-cancer ability, including growth inhibition and decrease the tumor volume in Xenograft model. However, there is no evidence for connection between PE and gastric cancer. Therefore, the aim of this study is to examine the effect of PE092002 on GC cells including N87 and AGS cells. In this study, PE reduced both GC cell line’s viability in MTT assay at 100 nM and 50nM. PE induced cell cycle arrest at G2/M phase by flow cytometry. Moreover, according to the result of Annexin V/PI double stain, early apoptosis level was enhanced in PE-treated GC cells. To detect the autophagy flux of autophagic vascular and acidic vesicular organelles (AVOs), we stained GC cells with MDC and acridine orange after the PE treatment and found that autophagy was induced by immunofluorescence. Furthermore, a autophagy inhibitor, bafilomycin A1, reversed the cytotoxicity of PE only in AGS cell. On western blot, PE treatment could increase the protein expression level of LC3 as well as reducing the p62 expression. Therefore, PE shows ability to induce autophagy in GC cells. Regarding to the kinases activation, Results showed that Akt/mTOR activation was inhibited, while MAPKs were phosphorylated. In a time-dependent manner. We found that ERK and JNK pathway were involved in PE-reduced Bcl-2 and apoptosis in N87 cells, while Akt/mTOR, ERK, and JNK were responsible for PE-affected LC3-II, p62, Bcl-2, autophagy following cell death through their pharmacological inhibitors. In conclusion, PE092002 could induces G2/M arrest, autophagy, apoptosis and cell death in GC cells, has the potential of GC treatment development.
論文目次 致謝 VI
章節目錄 VII
圖目錄 X
表目錄 XI
中文摘要 XII
Abstract XIV
縮寫表 XVI
第一章、 緒論 ( Introduction ) 1
1.1胃癌 ( Gastric cancer ) 1
1.1.1胃癌簡介 1
1.1.2胃癌成因及危險因子 2
1.1.3病理分期 2
1.1.4胃癌分類 5
1.2 現今胃癌的臨床治療方法 5
1.2.1手術治療(surgery) 5
1.2.2放射性治療 (Radiotherapy) 6
1.2.3化學藥物治療 6
1.2.4標靶藥物治療 7
1.3細胞週期與分裂 9
1.4細胞凋亡 11
1.5細胞自噬 12
1.6化合物PE092002 14
1.7研究動機 18
第二章、 實驗材料與方法 19
2.1實驗材料 19
2.1.1實驗藥品 19
2.1.2實驗套組 (kit) 20
2.1.3實驗抗體 (antibody) 20
2.1.4實驗用耗材及器材 20
2.1.5實驗儀器介紹:細胞分析儀 21
2.2細胞實驗 22
2.2.1細胞株及培養條件 22
2.2.2細胞繼代 (Cell culture) 22
2.3實驗方法 23
2.3.1細胞存活率與生長測定 (MTT assay) 23
2.3.2細胞週期分析 (cell cycle) 24
2.3.3 FITC Annexin V Apoptosis Detection 25
2.3.4西方墨點法 ( Western Blot ) 26
2.3.5 Monodansylcadaverine (MDC) 螢光染色 30
2.3.6 Acridine orange ( AO ) 螢光染色 30
2.3.7細胞轉染 ( transfection ) GFP-LC3 31
2.2.8統計分析 ( Statistic analysis ) 32
第三章、 實驗結果 33
3.1 PE092002 對人類胃癌細胞株 ( AGS、N87 cell )的細胞存活率試驗 33
3.2 PE092002 對人類胃癌細胞株細胞週期的影響 34
3.3 PE092002 對人類胃癌細胞株之細胞凋亡試驗 37
3.4 PE092002 造成細胞凋亡之探討 38
3.5 PE092002 誘導人類胃癌細胞中的細胞自噬反應 40
3.6 PE092002 影響細胞自噬相關蛋白變化 42
3.7 PE092002在人類胃癌細胞株AGS、N87中之調控機制探討 43
第四章、 討論 45
4.1 PE092002在胃癌細胞作用機轉探討 45
4.2細胞自噬的誘導所扮演的角色 47
4.3 AKT/mTOR與MAPKs調控影響之探討 49
4.4離體細胞實驗 ( in vitro ) 模式細胞之差異性比對 50
第五章、 結論 53
第六章、 圖表集 54
第七章、 參考文獻 73
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