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系統識別號 U0026-2107201712303500
論文名稱(中文) 三環抗憂鬱藥Imipramine在惡性腦神經癌幹細胞誘發之細胞死亡
論文名稱(英文) The Tricyclic Antidepressant Imipramine Induces Cell Death in Glioblastoma-derived Stem Cells
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 105
學期 2
出版年 106
研究生(中文) 陳菁麗
研究生(英文) Ching-Li Chen
電子信箱 s1003499@gmail.com
學號 s26044078
學位類別 碩士
語文別 英文
論文頁數 75頁
口試委員 指導教授-簡伯武
口試委員-張雅雯
口試委員-蕭雅心
中文關鍵字 惡性神經膠質瘤  癌幹細胞  靜安膜衣錠  細胞自噬  細胞凋亡  不健全自嗜通量 
英文關鍵字 CD133  glioblastoma  cancer stem cell  imipramine  autophagy  apoptosis  imipaired autophagic flux 
學科別分類
中文摘要 惡性神經膠質瘤為中樞神經系統中最常見且死亡率極高的一種原發性腦癌。目前研究指出癌症的再復發、抗放化療等問題與癌幹細胞有直接相關性。靜安膜衣錠是第一代三環抗憂鬱藥物,已證實具有抑制腦瘤細胞的生長,但對於惡性腦癌幹細胞之毒殺效果還尚未明確。本篇探討靜安膜衣錠治療惡性腦癌幹細胞之效果,及其中所誘發之細胞死亡機制。先前實驗已成功自人類惡性腦神經膠質瘤細胞株U87MG, 純化出帶有腦癌幹細胞特性之CD133+細胞。在本篇結果,顯示靜安膜衣錠具有毒殺腦癌幹細胞之能力,且效果優於帝盟多膠囊(TMZ)第一線化療用藥。靜安膜衣錠針對TMZ具抗性及TMZ +  放射線雙重抗性的U87MG細胞也具有顯著的毒殺效果。在腦癌幹細胞神經球體型態結果,所見靜安膜衣錠抑制腦癌幹細胞自我更新的能力。靜安膜衣錠不僅會誘發不健全自噬通量,透過給藥處理後的12小時開始p62的累積、48小時開始LC3-II的增加,於免疫螢光染色同樣觀察到綠螢光蛋白LC3聚集,呈現點狀分布。在給予氯喹(CQ),加重靜安膜衣錠所誘導的細胞死亡、p62堆積與LC3-II的蛋白質表達。反之, 加入3-甲基腺嘌呤(3-MA)細胞自噬抑制劑,可反轉靜安膜衣錠所誘發的不健全自噬通量、降低LC3-II與活化態凋亡蛋白酶-3的蛋白表達,及有腦癌幹細胞神經球體型態回復現象。另外,靜安膜衣錠處理腦癌幹細胞後第48小時,活化態的凋亡蛋白酶-3蛋白顯著增加、抗細胞凋亡蛋白Bcl-2顯著下降。氟甲基酮(Z-DEVD-FMK)或3-MA單獨投予,皆有明顯的減緩靜安膜衣錠所造成的細胞死亡,合併使用Z-DEVD-FMK及3-MA,更大幅度反轉靜安膜衣錠所造成的細胞死亡。綜合以上結果推論,細胞凋亡的活化,會強化靜安膜衣錠所誘發的不健全細胞自噬,所帶來的細胞死亡效果。腦癌幹細胞腫瘤異體移植模式下,證實靜安膜衣錠具抑制腦癌幹細胞生長與延長動物存活時間。總結,靜安膜衣錠具有抑制惡性腦癌幹細胞生長,經由誘發不健全自噬通量與細胞凋亡所造成。取其本身優越的通過血腦障壁能力,渴望能成為治療惡性腦癌幹細胞新方針。
英文摘要 Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumors of the central nervous system. Although the standard treatment are well-development, the median survival rate is still very short within 12 to 15 months. The CD133 glioblastoma-derived stem cells (GSCs) are responsible for chemo-/radiation-resistance and cancer recurrence. Recently, targeting on GSCs becomes an important part of the therapeutic strategies. Imipramine (Imi), a tricyclic antidepressant drug (TCA), has been reported to inhibit glioma cells growth. However, the effectiveness and underlying mechanism by which Imi inhibits GSCs progression remains unknown. Previously, our laboratory isolated GSCs with high expression of tumor stem cells marker CD133 from the U87MG cell line. In this study, treatment with Imi significantly decreased the cell survival of GSCs in a concentration-dependent manner. Imi also showed a significant cytotoxicity in the TMZ-resistant and TMZ plus  radiation-resistant U87 cells. In addition, a significant decrease in GSCs-derived neurosphere formation was observed in response to Imi treatment. Furthermore, we demonstrated that Imi increased the conversion of LC3-II within 48 h, increased p62 accumulation within 12 h and a significant increase in GFP-LC3 puncta formation within 48 h. Co-treatment with chloroquine, a lysosomal inhibitor, enhanced the Imi-induced cell death and Imi-induced expression of p62 and LC3-II in GSCs. In contrast, co-treatment with autophagy inhibitor 3-MA reversed the Imi-induced reduction in neurosphere formation. Similarly, the conversion of LC3-I to LC3-II and activation of caspase-3-induced by Imi were reversed by 3-MA. In addition, co-treatment with 3-MA attenuated the Imi-induced cell death. These results showed that Imi induced an impaired autophagic cell death. We further investigated whether the Imi-induced cell death was associated with apoptosis. We found that cleaved caspase-3 was detected after 48 h treatment with Imi. Combination of 3-MA and Z-DEVD-FMK could significantly reverse the effect of Imi on the survival of GSCs. Imi treatment significantly deceased the anti-apoptotic protein Bcl-2 expression, which further demonstrate the apoptosis was activated in response to Imi-induced cell death. We further investigated the anti-tumor activity of Imi in vivo. The results revealed that Imi significantly reduced the tumor growth, prolonged the survival time and prevented the body weight loss in the Imi-treated animals compared with vehicle group.
In summary, we have demonstrated Imi inhibited GSCs proliferation in vitro and in vivo, which was mediated by the induction of autophagic and apoptotic cell death. With the advantage of being able to cross the blood-brain barrier, we suggest Imi may be used to combine with the standard treatment for curing the GBM.
論文目次 中文摘要 Abstract in Chinese 1
英文摘要 Abstract in English 4
誌謝 Acknowledgement 7
縮寫檢索表 Abbreviations 9
圖表索引 List of Figures 11
Chapter 1 Introduction 14
Chapter 2 Specific Aims 29
Chapter 3 Materials and Methods 31
Chapter 4 Results 40
Chapter 5 Discussion 61
References 66
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