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系統識別號 U0026-0908201614221300
論文名稱(中文) 米諾環素合併 STAT3 抑制劑降低惡性神經膠質瘤之形成
論文名稱(英文) Combination of minocycline with STAT3 inhibitor suppresses glioma cell-derived tumorigenicity
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 104
學期 2
出版年 105
研究生(中文) 張家馨
研究生(英文) Chia-Hsin Chang
學號 s26034015
學位類別 碩士
語文別 英文
論文頁數 57頁
口試委員 指導教授-簡伯武
口試委員-林惠菁
口試委員-陳柏熹
中文關鍵字 神經膠質瘤  幹細胞  米諾環素  訊息傳遞轉錄活化基因-3  合併治療  細胞凋亡 
英文關鍵字 glioma/ cancer stem cell/ minocycline  STAT3  combination therapy  apoptosis 
學科別分類
中文摘要 惡性神經膠質瘤(Glioblastoma Multiform, GBM)是一種死亡率極高的中樞神經性腫瘤。目前研究指出腫瘤的抗藥性和幹細胞(stem cell)相關,而惡性神經膠質瘤幹細胞(Glioma stem cells, GSCs)被認為和腫瘤復發及抗藥性的關聯性很大。米諾環素(Minocycline, Mino)是四環黴素衍生物抗生素,實驗室先前研究也發現米諾環素藉由內質網壓力,導致自噬作用(autophagy)以抑制惡性神經膠質瘤生長,但米諾環素卻對抑制惡性神經膠質瘤幹細胞生長的能力差。為針對幹細胞治療,先前研究訊息傳遞轉錄活化基因-3 (signal transducer and activator of transcription 3; STAT3)高度表達於癌症幹細胞中,並影響神經膠質瘤幹細胞的存活率。故將深入探討合併米諾環素與STAT3抑制劑,可否能更有效抑制惡性神經膠質瘤生長。
我們將人類惡性神經膠質瘤細胞株U87,純化出 CD133+及CD133-,觀察到CD133+細胞也會表現其他幹細胞的蛋白及低劑量的CD133+細胞便足以在動物裡形成腦瘤。根據細胞存活率實驗,米諾環素對CD133-腦瘤細胞的抑制能力較大,而STAT3抑制劑對CD133+腦瘤幹細胞的抑制能力較大。根據此結果合併米諾環素及STAT3抑制劑,發現對於抑制腦瘤細胞存活率具有加成作用,且低劑量的合併治療效果,比現今惡性神經膠質瘤第一線用藥temozolomide (TMZ) 100 µM更為顯著。進而探討在腦瘤動物模式裡的治療效果,發現在動物實驗裡,相較於單獨使用任一藥物,合併治療具有顯著的加成效果。根據西方墨點法得知,米諾環素合併STAT3抑制劑是藉由增加caspase 3的活性,使細胞凋亡(apoptosis)為參與其中之程序性細胞死亡。
綜合以上實驗結果得知,合併使用米諾環素與STAT3抑制劑具有在細胞實驗及腦瘤動物模式裡皆具有顯著的抗癌效果,期待未來能成為治療惡性神經膠質瘤一個新的方向。
英文摘要 Glioblastoma Multiforme (GBM) is the most common incurable primary brain tumor of the central nervous system. Glioma stem cells (GSCs) are thought to contribute to recurrence and drug resistance in GBM. Minocycline (Mino) is a semisynthetic tetracycline derivative with bacteriostatic activity. Our laboratory has reported that Mino induces glioma cells endoplasmic reticulum stress resulting in autophagic cell death. However, GSCs exhibited higher drug resistance to Mino than Non-GSCs did. Signal transducer and activator of transcription 3 (STAT3) affect neurosphere formation and cell viability in GSCs. In this study, I hypothesized that combination of Mino with STAT3 inhibition exhibited more effective in the treatment of GBM.
I isolated GSCs from human primary glioblastoma cell line U87 using CD133 as a cancer stem cell marker. These CD133+ glioma cells exhibited self-renew property and expressed stem cell markers in vitro, promoted tumor formation in vivo. Mino reduced the survival rate more in CD133- than in CD133+ cells. In contrast, STAT3 inhibitor was more effective in reducing the survival rate of CD133+. Combined treatment with Mino and STAT3 inhibitor synergistically reduced the cell viability of glioma cells. Transduced glioma cells were injected intracranially into athymic mice and tumor growth was monitored using the IVIS-200 imaging system. Combination therapy of Mino plus STAT3 inhibitor synergistically inhibited tumor growth in nude mice. Furthermore, I found that combined treatment-induced cell death involved caspase-dependent apoptosis at 48 hr.
These findings provide the evidence that the combination of Mino and STAT3 inhibitor significantly decrease cell viability in vitro and in vivo. It suggests that additional targeting STAT3 may provide an effective combination therapy for patients with malignant glioma.
論文目次 中文摘要 (Abstract in Chinese)…………………………………………………………....I
英文摘要 (Abstract in English)…………………………………………………………..IV
致謝 (Acknowledgement) ………………………………………………………….........VII
目錄 (Outline)…………………………………………………………………………..VIII
圖表索引 (List of Figures)……………………………………………………….………IX
縮寫檢索表 (Abbreviations)…………………………………………………………..…XI
Chapter 1: Introduction………………………………………………………...……….......1
Chapter 2: Specific Aims………………………………………………………………..…16
Chapter 3: Materials and Methods…………………………………………………….…..18
Chapter 4: Results…………………………………………………………………………25
Chapter 5: Discussion……………………………………………………………………..42
參考文獻 (References)……………………………………………………………….…..48

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