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研究生:李健如
研究生(外文):Chien-Ju Lee
論文名稱:探討杜松子粗萃物對大腸直腸癌之抑癌作用
論文名稱(外文):To investigate the tumor suppression effects of JCo extract in colorectal cancer in vitro and in vivo
指導教授:蔡女滿
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學檢驗暨生物技術學系碩士班
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:98
中文關鍵詞:大腸直腸癌5-FUVP-16杜松子粗萃物細胞週期細胞凋亡
外文關鍵詞:Colorectal cancer5-FUVP-16JCo extractCell cycleApoptosis
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大腸直腸癌發生率在全球、美國及台灣都排名第三名。臨床上除了手術切除之外,普遍使用化療藥物作為治療方式,其中,5-FU及VP-16為癌症常見臨床用藥,而5-FU更是大腸直腸癌一線用藥之一,主要機制是與酵素Thymidylate synthase結合並抑制其作用,使Thymidylate無法合成而產生DNA damage,此過程同時會造成體內正常細胞遭受破壞,進而產生病人強烈的副作用。杜松子粗萃物為天然植物萃取液,傳統醫療使用上對人體的傷害性低,根據目前研究指出,杜松子粗萃物可以促使多種腫瘤細胞細胞週期停滯,可能具有抗癌功效,但詳細機制仍尚未明瞭。本篇論文目的為探討杜松子粗萃物於體內及體外對大腸直腸癌之抑癌作用及機轉。首先,測試藥物對細胞之毒性,得知杜松子粗萃物能抑制大腸直腸癌細胞生長,且對正常細胞毒性較臨床藥物5-FU及VP-16低,並與5-FU合併作用下具協同作用,進一步研究發現,杜松子粗萃物會誘發p53磷酸化,增加p21蛋白表達,使細胞週期運行停滯於G0/G1 phase,並且隨著處理時間及劑量增加,產生Sub-G1的死亡細胞百分比呈現增加趨勢,同時證實杜松子粗萃物會啟動內在及外在細胞凋亡路徑,誘發大腸直腸癌細胞死亡,並抑制腫瘤血管新生及轉移相關蛋白表達。在動物實驗中,杜松子粗萃物可以有效抑制體內大腸直腸癌腫瘤生長及延長動物存活時間,並且抑制體內腫瘤細胞細胞週期運行且活化Caspase-3促使細胞凋亡,同時降低腫瘤血管生成及轉移蛋白表達量。綜合上述,杜松子粗萃物於體外及體內都能有效抑制大腸直腸癌之細胞生長,促使細胞週期運行停滯,同時誘發腫瘤細胞凋亡而達到抑制腫瘤生長之功能。因此,杜松子粗萃物具有高度潛力能夠開發為治療大腸直腸癌之抗癌藥物。

Colorectal cancer (CRC) is one of the major cause of morbidity and mortality from cancers worldwide. The incidence of colorectal cancer is ranking third in the United States and Taiwan. 5-FU and VP-16 are major clinical chemodrugs for cancer therapy, especially 5-FU, which is one of the first-line chemotherapy regimens for colorectal cancer treatment. As its mechanism, 5-FU binds to thymidylate synthase and inhibits its synthesis, further reduces DNA synthesis and metabolism. However, the process also causes normal cells destruction and induces strong side effect. Plant extract JCo is a natural crude from steam distillation and extraction. It is less harmful and use in the traditional medicine for a long time. Furthermore, recent studies show that JCo extract can induce cell cycle arrest in several cancers, but the detail mechanism is still unclear. The purpose of this study is to investigate the anti-cancer effects of JCo extract in colorectal cancer in vitro and in vivo. In the study, JCo extract could inhibit colorectal cancer cells growth, and had lower cytotoxicity than 5-FU and VP-16 in normal cells. In addition, JCo extract could induce cell cycle arrest at G0/G1 phase, and induced both extrinsic and intrinsic cell apoptosis pathways to cause cell death. In animal study, JCo extract could suppress tumor growth and prolong animal survival time. It also had low or no physiological and pathological toxicity to normal organ. Moreover, it could reduce tumor angiogenesis and metastasis related proteins expression in vivo. In conclusion, JCo extract could induce cell cycle arrest, trigger cell apoptosis to inhibit cell proliferation, reduce tumor angiogenesis and metastasis related protein expression in vitro and in vivo. Consequently, JCo extract has highly potential to develop an anti-cancer agent in colorectal cancer therapy.

致謝………………………………………………………………………………i
中文摘要……………………………………………………………………ii
英文摘要……………………………………………………………………iii
縮寫表…………………………………………………………………………iv
目錄………………………………………………………………………………v
圖表目錄……………………………………………………………………viii


壹、前言………………………………………………………………………………1
一、大腸直腸癌 (Colorectal cancer)……………1
二、杜松子粗萃物 (Juniperus communis)……4
三、5-Fluorouracil (5-FU)…………………………………6
四、Etoposide (VP-16)……………………………………………6
五、藥物協同作用 (Drug Synergism)………………7
六、細胞週期 (Cell cycle)……………………………………7
七、細胞凋亡 (Apoptosis)………………………………………10
八、失巢凋亡 (Anoikis)……………………………………………13
九、血管新生 (Angiogenesis)………………………………14
十、細胞轉移 (Metastasis)……………………………………16
十一、實驗目的…………………………………………………………………18
十二、實驗策略…………………………………………………………………18


貳、材料與方法…………………………………………………………………20
一、植物粗萃物…………………………………………………………………20
二、細胞株與細胞培養……………………………………………………20
三、利用MTT assay 觀察JCo extract對細胞抑制生長情形以及合併臨
床藥物抑制細胞生長之協同作用………………………21
四、利用流式細胞儀分析JCo extract對細胞週期之影響……………23
五、利用TUNEL assay偵測JCo extract誘發細胞凋亡現象………24
六、觀察JCo extract誘發細胞週期調控因子及細胞凋亡相關蛋白之表現
情形…………………………………………………………………………………27
6-1. 以JCo extract及細胞凋亡抑制劑處理細胞……27
6-2. 蛋白質萃取…………………………………………………………………29
6-3. 以BCA assay測定蛋白質濃度……………………………29
6-4. 西方點墨法…………………………………………………………………30
七、建立人類結腸直腸癌化學治療之動物模式………32
7-1. 人類結腸直腸癌之治療模式…………………………………32
7-2. Hematoxylin and Eosin stain (HE stain)……………32
7-3. Immunohistochemistry stain (IHC stain)……………33
7-4. Quick score及PCNA半定量及血管計數………………………………34
八、統計分析…………………………………………………………………………35

參、結果………………………………………………………………………………36
一、測試JCo extract及臨床藥物對大腸直腸癌細胞之抑制生長情形 ………………………………………………………………………………36
二、比較JCo extract及臨床藥物之IC50濃度………………………………38
三、測試JCo extract與合併臨床藥物5-FU處理之協同作用……40
四、比較JCo extract對HT-29細胞株之細胞週期運行之影響…41
五、觀察JCo extract誘發HT-29細胞株之細胞凋亡現象……………42
六、分析JCo extract誘發HT-29細胞株之抗癌機制………………………43
七、觀察JCo extract抑制人類大腸直腸癌之動物治療模式………46
八、探討JCo extract對人類大腸直腸癌之抗癌作用機轉……………48
肆、討論……………………………………………………………………………51
伍、結論……………………………………………………………………………56
參考文獻……………………………………………………………………………58


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