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研究生:白惠珍
研究生(外文):Hui-Chen Pai
論文名稱:Moscatilin及其衍生物MT-4在人類乳癌與卵巢癌之抗癌作用機轉探討
論文名稱(外文):Investigation of the anti-cancer mechanisms of Moscatilin and MT-4 in human breast and ovarian cancer
指導教授:鄧哲明鄧哲明引用關係
口試委員:黃德富顏茂雄楊春茂
口試日期:2015-05-11
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:105
中文關鍵詞:石斛抗藥性轉移
外文關鍵詞:Moscatilinepithelial–mesenchymal transitionmultidrug-resistant
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癌症一直是十大死亡因素之首,根據台灣衛生福利部國民健康署統計,癌症是十大死因之首,在女性十大癌症死亡率排行中,乳癌與卵巢癌分別位居第四名和第八名。為了有效治療癌症,抗癌藥物開發在治療癌症是相當重要的議題。本篇研究論文的主軸,為探討中草藥萃取物質 moscatilin及其衍生物 MT-4 來治療癌症,並對作用藥理機轉進行研究。
本篇論文第一部分,我們主要探討黃草石斛 (Dendrobriumloddigesii)莖部萃取物 moscatilin對於人類高度轉移性乳腺癌細胞株 (MDA-MB-231)其細胞爬行及遷移能力的機轉探討。上皮-間質轉型 (epithelial–mesenchymal transition)過程對於癌細胞轉移是很重要的步驟,其中需要Twist和 Snail轉錄因子及Akt蛋白參與。Moscatilin抑制乳癌細胞轉移是透過降低Twist蛋白和mRNA的表現,導致下游訊息傳遞路徑的N-cadherin蛋白減少,但是 moscatilin不影響 Snail轉錄因子的蛋白表現量。由這些結果得知moscatilin抑制乳癌細胞爬行與遷移是分別透過抑制Twist和Akt訊息傳遞路徑來。在活體進行腫瘤轉移動物模式實驗,也證實moscatilin有效抑制癌細胞轉移。綜合以上實驗結論, moscatilin對於預防人類乳癌轉移或許是一個有效的compound。
論文的第二部分,我們更進一步在試管內及活體實驗,探討moscatilin衍生物 MT-4的抑制卵巢癌生長的機轉作用研究。 我們發現MT-4導致癌胞凋亡是透過活化P38 MAPK訊息傳遞路徑。最重要的結果是MT-4 也可以抑制HSP27 蛋白表現,進而降低與caspase-3結合,而這些都與化療抗藥性有高度相關。以上結果指出,MT-4具有潛力成為lead compound對於治療多重抗藥性的卵巢癌細胞。
綜合以上所述,本論文主要證實 moscatilin及其衍生物 MT-4 具有特殊的作用機轉,能做為具有研發潛力,成為癌症治療的先導藥物。


According to Health Promotion Administration, Ministry of Health and Welfare in Taiwan, cancer has been the first place of ten leading deaths. Breast and ovarian cancer are the fourth and eighth common type in female and often seen in cancer-related death in Taiwan. In order to cure cancer efficaciously, anticancer drugs development is an important issue in cancer therapy. In this thesis, the anticancer mechanisms of moscatilin which is isolated from the stem of the orchid Dendrobriumloddigesii and MT-4 were examined in human breast cancer and ovarian cancer, respectively.
In the first part of the thesis, we evaluated the mechanism of moscatilin in suppressing the migration and metastasis of human breast cancer MDA-MB-231 cells. Transcriptional factors inducing epithelial–mesenchymal transition (EMT), such as Twist, Snail, and Akt, plays important roles in cell migration and cancer metastasis.Moscatilin inhibited the mRNA and protein expression of Twist, but not that of Snail, and subsequently inhibited N-cadherin expression. These results indicated that moscatilin inhibited migration via Akt- and Twist-dependent pathways; this finding was consistent with moscatilin’s antimetastatic activity in vivo. Therefore, moscatilin may be an effective compound for the prevention of human breast cancer metastasis.
In the second part of thesis, we evaluated the activity of MT-4 in vitro and in vivo xenograft assays.We found that p38 MAPK pathway activation was involved in MT-4-induced apoptosis. Most importantly, MT-4 also decreased heat shock protein27 expression and reduced its interaction with caspase-3, which inured cancer cells to chemotherapy resistance. These findings indicate that MT-4 could be a potential lead compound for the treatment of multidrug-resistant ovarian cancer.
Take together, our results demonstrated that moscatilin and MT-4 have unique properties and may be a potential and promising anti-cancer therapeutic option.


口試委員審定書……………………………………………………………………….………………..…..…………I
致謝…………………….…………………………………………………………………….…………….……….……….II
Abbreviations………………………………………………….………………………….…………….………….....IV
Abstract……………………………………………………………………………………………….…..……………..…V
Abstract in Chinese (中文摘要)………………………………………………………………………….…..VII
Chapter I : Introduction
Breast cancer………………………………………………………………………………………..……..........1
Ovarian cancer………………………………………………………………………………………..….……....2
Epithelial-mesenchymal transition (EMT) and metastasis……………………….……..…...3
Drug resistance……………………………………………………………………………………………....…..5
Role of P38 in cancers………………………………………………………………….………………..……6
Heat shock protein 27………………………………………………………………….……………...……...7
Apoptosis……………………………………………………………………………….……………….………....8
Aims of thesis……………………………………………………………………………..………..…..…….….9
Chapter II: Moscatilin Inhibits Migration and Metastasis of Human Breast Cancer MDA-MB-231 Cells through Inhibition of Akt and Twist Signaling Pathway……………………………….……………..………………………………….….…………25

Chapter II: MT-4 suppresses resistant ovarian cancer growth through targeting tubulin and HSP27………………………………….……………………………………….…55

Chapter IV: Conclusion and perspective………………………….………………………….....….…93
Publications……….………………………….…………………….……………………..………..….…...….....…97
References..………….……………….………………………………………………………………..…….…….…101



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