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研究生:李慧穎
研究生(外文):Huey-Yin Lee
論文名稱:苦橙果皮萃取物誘導人類肝癌細胞自體吞噬達到抑癌效果
論文名稱(外文):Bitter Orange Peel Extract Induces Autophagy In Human Hepatoma Cells
指導教授:沈立言沈立言引用關係
指導教授(外文):Lee-Yan Sheen
口試委員:何其儻鍾景光李宗貴謝淑貞
口試委員(外文):Chi-Tang HoJing-Gung ChungChong-Kuei LiiShu-Chen Hsieh
口試日期:2015-07-14
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:食品科技研究所
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:121
中文關鍵詞:肝癌苦橙果皮萃取物多甲氧基黃酮自體吞噬合併功效
外文關鍵詞:liver cancerbitter orange peel extractpolymethoxyflavonesautophagycombination effect
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肝癌於全球人類癌症致死率排名第二位,由於現行的治療方法效力不佳,目前肝癌患者的五年相對存活率僅16%,因此許多患者嘗試以天然成分作為佐劑,希望能提高傳統療法的療效並減緩其副作用。柑橘類水果為全球重要的農產品之一,除作為新鮮水果食用之外,剩餘的果皮則可開發成為副產品。柑橘類果皮含有多種黃酮類成分,而多甲氧基黃酮為其特有的成分,過去研究發現此類化合物具有抗氧化、抗發炎及減緩脂肪堆積等生理活性,近來其抗癌效果亦受到重視。本研究利用苦橙果皮經超臨界萃取所得之果皮萃取物(bitter orange peel extract, BOPE),探討其對人類肝癌Hep 3B細胞的抑癌機制,及其主要成分的合併作用。細胞存活率結果顯示在BOPE的處理下可顯著抑制人類肝癌細胞的增殖,形態上可觀察到細胞內產生空泡化現象。細胞免疫染色結果發現BOPE使自噬小體形成的重要指標蛋白LC3在細胞中有聚集的現象,且西方墨點法的結果亦顯示LC3-II表現量隨BOPE的處理有顯著性上升,故判定BOPE可經由誘導細胞產生自噬作用(autophagy)而達到抑制效果。深入探討其分子機制發現,BOPE首先可促進Hep 3B細胞大量產生ROS及降低ATP水平而導致內質網壓力的發生。內質網壓力的增加促使內質網中的鈣離子大量釋放到細胞質中,進一步活化下游的AMPK、TSC2,抑制mTOR活性,並且活化DAPK及Beclin-1,最終導致自體吞噬。而HPLC分析結果顯示BOPE中主要成分為橘皮素及川陳皮素,為了進一步了解橘皮素及川陳皮素兩者間的作用方式,將兩者進行單獨處理及共同處理之下發現後者對於細胞的抑制效果更佳。以不同比例將橘皮素與川陳皮素共同培養觀察其對細胞存活率的影響,並透過合併指數(combination index, CI)的換算發現兩者的確發揮協同效果(synergistic effect)。綜合上述結果,苦橙果皮萃取物可藉由誘導人類肝癌細胞產生內質網壓力調節之自體吞噬達到抑癌效果,且其主成分橘皮素與川陳皮素扮演者協同性作用,具有輔助抗癌治療之潛力。

Liver cancer is the second major cancer related death in the world. There are only 16% of 5-year relative survival rate among liver cancer patients because of the poor prognosis and cancer therapy side effects. To relieve the uncomfortable symptoms, natural adjuvant has become an alternative trend instead of conventional treatment. Polymethoxyflavones (PMFs) are a group of flavones found in citrus fruits peel. Tangeretin and nobiletin are major compounds in PMFs which their potential biological activities have been reported, such as anti-inflammation, anti-diabetes and anti-cancer. The objectives of this study are to investigate the anti-liver cancer activity of bitter orange peel extract (BOPE) and its molecular mechanisms in human hepatoma Hep 3B cells. The results showed that BOPE effectively reduced Hep 3B cell viability with the IC50 of 48.95 μg/mL at 24 hours. In addition, BOPE induced LC3 aggregation and conversion of LC3-I to LC3-II, which required for autophagosome formation, without increasing hypodiploid proportion and plasma membrane leakage. These results demonstrated that BOPE induced cell death of Hep 3B cells by autophagy rather than apoptosis and necrosis. In this study, we also investigated the molecular mechanisms of BOPE-induced cell autophagy. Results showed that BOPE promoted ROS generation and ATP depletion in Hep 3B cells, leading to ER stress, following by elevatation of cytosolic calcium ion concentration and activation of AMPK/TSC2/mTOR and DAPK/Beclin-1 pathways. Furthermore, major components of BOPE, tangeretin and nobiletin, exhibited synergistic effect to inhibit cell viability in Hep 3B cells. In conclusion, tangeretin and nobiletin from BOPE can synergistically induce ER-stress mediated cell death by autophagy in human hepatoma Hep 3B cells and it could be used as a potential complementary agent for liver cancer therapy.

謝誌 I
中文摘要 II
Abstract III
縮寫對照表 V
目錄 X
圖次 XIV
表次 XVI
第一章、文獻回顧 1
第一節、肝臟與肝癌 1
一、肝臟 1
二、癌症與肝癌 4
三、肝癌致病機轉與因子 7
四、肝癌治療方法 10
第二節、細胞死亡(Cell death) 12
一、細胞凋亡(Apoptosis) 14
二、細胞自體吞噬(Autophagy) 18
三、細胞壞死(Necrosis) 23
四、有絲分裂崩潰(Mitotic catastrophe, MC) 24
第三節、內質網壓力 25
一、內質網壓力 25
二、內質網壓力誘導自體吞噬的訊息傳遞途徑 25
第四節、柑橘(Citrus) 29
一、柑橘之基本介紹 29
二、柑橘活性成分 31
三、多甲氧基黃酮(Polymethoxyflavones, PMFs) 32
四、多甲氧基黃酮之生理功效 35
第五節、藥物合併作用(Drug combination effects) 38
第二章、假說與目的 39
一、假說 39
二、目的 40
第三章、實驗架構 41
第四章、實驗材料 42
第一節:藥品與儀器 42
一、藥品 42
二、儀器 44
第二節:樣品與細胞株 46
一、樣品 46
二、細胞株 46
第五章、實驗方法 47
第一節:樣品製備與分析 47
一、樣品製備 47
二、高效液相層析分析 47
第二節:細胞培養與抗增殖活性探討 48
一、細胞培養條件 48
二、細胞繼代 48
三、細胞冷凍保存 48
四、細胞解凍 49
五、細胞計數 49
六、細胞存活率(Cell viability)分析 51
第三節:細胞死亡模式之探討 52
一、細胞形態觀察(Cell morphology determination) 52
二、細胞大小及顆粒性分析(Cell size and granularity analysis) 53
三、乳酸去氫酶釋放試驗(LDH leakage assay) 54
四、細胞核質濃縮(Nuclear condensation)之觀察 55
五、亞二倍體比例(Hypodiploid phase)之分析 56
六、Annexin V-FITC/PI 雙染分析(Annexin V-FITC/PI double staining) 57
七、LC3分佈之觀察(LC3 distribution determination) 58
第四節:細胞自體吞噬之機制探討 59
一、活性氧物質生成分析(ROS generation analysis) 59
二、三磷酸腺苷含量分析(ATP level determination) 60
三、鈣離子位移分析(Calcium mobilization) 61
四、西方墨點法(Western blotting) 62
第五節:資料統計 67
第六章、結果與討論 68
第一節:樣品成分分析 68
第二節:抗癌活性評估 69
一、苦橙果皮萃取物對Hep 3B細胞存活率之影響 69
二、本節討論 69
第三節:細胞死亡模式分析 71
一、苦橙果皮萃取物對Hep 3B細胞形態之影響 71
二、苦橙果皮萃取物對Hep 3B細胞受損程度之影響 71
三、苦橙果皮萃取物對Hep 3B細胞染色質濃縮程度之影響 72
四、苦橙果皮萃取物對Hep 3B細胞亞二倍體比例之影響 72
五、苦橙果皮萃取物對Hep 3B細胞Phosphatidylserine(PS)外翻之影響 73
六、苦橙果皮萃取物對Hep 3B細胞自噬體形成之影響 73
七、本節討論 74
第四節:細胞自噬機制探討 75
一、苦橙果皮萃取物對Hep 3B細胞活性氧物質生成及三磷酸腺苷水平之影響 75
二、苦橙果皮萃取物對Hep 3B細胞鈣離子訊號之影響 76
三、本節討論 77
第五節:成分交互作用之探討 78
一、橘皮素與川陳皮素交互作用之探討 78
二、本節討論 79
第六節:綜合討論 80
第七節:未來研究 82
一、苦橙果皮萃取物之後續抗癌研究 82
二、多甲氧基黃酮成分對抑癌機制的研究 83
第七章、結論 84
第八章、實驗圖表 86
第九章、參考文獻 105
第十章、附錄 119

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