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系統識別號 U0026-2807201414014800
論文名稱(中文) 探討合成咔唑類衍生物DSF-1b抗神經膠質瘤之作用機轉
論文名稱(英文) Biological Evaluation of DSF-1b, a Synthetic Carbazole Derivative, as an Anti-glioma Drug
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 102
學期 2
出版年 103
研究生(中文) 花國書
研究生(英文) Kuo-Su Hua
學號 S26011017
學位類別 碩士
語文別 英文
論文頁數 60頁
口試委員 指導教授-簡伯武
口試委員-陳柏熹
口試委員-張雋曦
中文關鍵字 惡性神經膠質瘤  咔唑類衍生物  細胞凋亡  自噬作用  內質網壓力 
英文關鍵字 Malignant glioma  Carbazole derivative  Apoptosis  Autophagy  Endoplasmic reticulum stress 
學科別分類
中文摘要 惡性神經膠質瘤是一種高度侵犯性的腦瘤,也是公認最致命的癌症之一。雖然現今的醫療水平已有所進步,但腫瘤的抗藥性及再復發性仍對臨床治療帶來巨大挑戰。據統計,惡性神經膠質瘤患者平均存活時間僅約15個月,而五年存活率則不到百分之五,因此,開發新穎的治療策略針對惡性神經膠質瘤是非常重要的議題。咔唑是一類富含於芸香科植物中的多環含氮化合物。過去的文獻指出,咔唑類衍生物具有抑制多種腫瘤生長的能力,然而,其抑制惡性神經膠質瘤的能力及機轉仍不甚清楚。在本篇研究中,我們針對16種咔唑類衍生物進行抗癌活性的篩選,發現代號DSF-1b的化合物對於三株惡性神經膠質瘤細胞:C6、U251、T98G的增殖能力,皆具備著最低的半抑制濃度,而此作用濃度對正常神經膠細胞產生的傷害非常有限。藉由細胞存活試驗與直接細胞計數的方法,我們得知DSF-1b在抑制癌細胞生長的同時,也會造成癌細胞死亡。我們更進一步利用流式細胞儀分析,證明了DSF-1b會使此三種癌細胞分裂週期停滯於G2/M期,進而抑制癌細胞生長。值得注意的是,隨著藥物處理時間拉長至48小時,U251和T98G的細胞週期會逐漸往sub-G1期分布,而C6在同一時間點並沒產生類似的現象。我們緊接著使用兩種細胞凋亡的試驗去驗證此sub-G1族群是否為凋亡的細胞。結果顯示,在藥物處理48小時後,U251和T98G會產生明顯的caspase活化及DNA濃染,而C6則無。另一方面,我們在西方墨點法及免疫螢光染色的實驗中,發現C6會在處理藥物24小時後開始產生自噬作用。有趣的是,若我們對C6前處理3-MA(自噬作用抑制劑),則C6在接觸到DSF-1b後便會產生明顯的細胞死亡,且此時C6的DNA也會變得濃染,並伴隨著活化態caspase的生成。此外,我們也探討了調控自噬作用發生的上游訊息傳遞路徑,我們發現C6會在DSF-1b處理8小時後,產生明顯的內質網壓力,藉由自噬作用與內質網壓力發生時間點的先後順序,我們認為DSF-1b在C6中所引發的內質網壓力與後續自噬作用的產生,有著上下游調控關係的存在。總結來說,本篇實驗證明咔唑類衍生物DSF-1b可以藉由干擾細胞週期及促進細胞凋亡的方式抑制惡性神經膠質瘤細胞的存活。而在C6中,細胞會在面對藥物時,持續維持於一個細胞週期停滯的狀態,並產生自噬作用使自己有限度的存活。一旦細胞無法產生自噬作用,則藥物會使其走向凋亡。
英文摘要 Malignant glioma is considered to be the deadliest cancer type as it is highly invasive and neurologically destructive. Despite decades of concerted effort and technological advances in neurosurgery, radiotherapy and chemotherapy, the therapeutic resistance and tumor recurrence still result in dismal prognosis with a five year survival rate of less than 5%. Therefore, developing a novel agent for treating malignant glioma is particularly imperative. Carbazole, a group of aromatic tricyclic compounds naturally occurred in Rutaceae plants, has first been extracted in 1872. Its derivatives have been proposed to exert anti-proliferation activity against several types of cancers. However, the effectiveness and underlying mechanism by which carbazole derivatives inhibit malignant glioma progression remains poorly clarified. Here, we screened 16 novel synthetic carbazole derivatives for their cytotoxic effects against three glioma cell lines, and found DSF-1b to be the most potent compound. Using both cell proliferation and direct cell counting, we further showed that DSF-1b not only attenuated glioma cell growth but also induced cell death while caused minimal harm to normal glia. An interrupted cell cycle that failed to pass G2/M checkpoint was observed in all glioma cell lines. However, elevated percentage of cells in the sub-G1 phase within 48 hours was detected in U251 and T98G glioma but much less in C6 glioma. This observation was consistent with the level of apoptotic hallmarks: caspase activation and chromatin condensation. On the other hand, Western blotting and immunofluorescent staining showed that C6 glioma underwent autophagy at 24 hours after DSF-1b treatment. Interestingly, ablation of DSF-1b-induced autophagy did not affect overall C6 glioma survival but induce cell death. Besides, above-mentioned apoptotic hallmarks were increased in C6 glioma pretreated with 3-MA. Furthermore, we also found that DSF-1b-induced ER stress was triggered before autophagy, indicating ER stress may account for the DSF-1b-induced autophagy. In conclusion, our data demonstrated that DSF-1b inhibits three glioma cell lines growth by interfering cell cycle progression and inducing apoptosis. In case of C6 glioma, cell will stay in a non-proliferating stage and alleviate cytotoxic stress by triggering ER stress-associated autophagy.
論文目次 中文摘要(Abstract in Chinese) I
英文摘要(Abstract in English) IV
誌謝 VII
目錄(Contents) VIII
圖索引(List of Figures) IX
Chapter 1 Introduction 1
Chapter 2 Specific aims 18
Chapter 3 Materials and Methods 20
Chapter 4 Results 26
Chapter 5 Discussion 34
References 40
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