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研究生:鍾秀昌
研究生(外文):HSIU-CHANG CHUNG
論文名稱:能誘發神經母細胞瘤SHSY5Y細胞自噬之抗有絲分裂藥物Combrestastatin A-4衍生物之篩選
論文名稱(外文):Screening of Antimitotic Drug Combretastatin-A4 Derivatives That Are Capable of Inducing Autophagy in Neuroblastoma SHSY5Y Cell Line
指導教授:陳錦翠
指導教授(外文):Jiin-Tsuey Cheng
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2013
畢業學年度:102
語文別:中文
論文頁數:74
中文關鍵詞:p62LC3-II有絲分裂細胞自噬Combrestastatin A-4
外文關鍵詞:Combrestastatin A-4autophagyLC3-IIp62mitosis
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細胞自噬作用為清除胞內異常聚集蛋白及受損胞器,以回收再利用細胞資源的一種維持細胞生理恆定之重要機制。當細胞受到內、外壓力時,會啟動細胞自噬幫助細胞之生存。因此,異常的細胞自噬作用在諸如癌症、病原感染及神經退化性疾病致病上扮演極重要之角色。細胞自噬作用過程中藉由自噬體與溶酶體融合形成自噬溶酶體,並藉由酵素分解其內容物再利用。許多研究顯示,微管系統會參與將自噬體運送至溶酶體,或後期內含體的過程。因此,微管系統之動態平衡與細胞自噬作用正常運作有著密切的相關性。Combretastatin A-4 (簡稱CA-4)是一種具有抗微管聚合作用之天然化合物,具有抗腫瘤與抑制血管新生的能力,但CA-4藥物水溶性較差,故難以充分發揮其藥效作用。許多科學家針對結構簡單的CA-4天然物進行結構修飾及改造,期望能獲得生物活性更好及水溶解度提升之衍生物。本研究針對國立中山大學化學系吳明忠教授實驗室所合成的一系列新型CA-4烯雙炔衍生物,分別探討其細胞致死劑量IC50作用下對於神經母細胞瘤SHSY5Y及肝癌Hep3B是否與CA-4藥物類似,具有抑制微管聚合之特性。研究顯示九種新型衍生物中LO-OMe、LO-NH2、LO-py及HYH10f皆具有與CA-4控制組類似之抗微管效應。本研究亦利用流式細胞儀分析其是否會造成SHSY5Y細胞生長週期的變化,結果指出,具有抑制微管聚合之衍生物LO-OMe、LO-NH2及HYH10f皆與控制組CA-4一樣會導致細胞週期停滯於G2/M期。其餘新型烯雙炔之衍生物CPC14c、CPC20a、CPC15a、CPC19a及HYH10a其對微管形成及細胞週期皆無顯著作用活性。此結果顯示在各種不同位置修飾取代之烯雙炔衍生物對於神經母細胞株之抗微管聚合及細胞週期之效應不同。因微管與細胞自噬作用息息相關,且CA-4之烯雙炔類衍生物對於細胞自噬作用之調節仍未有文獻報導,因此本研究首先以細胞自噬標幟蛋白LC3-II及p62蛋白為監控對象,分析此群烯雙炔衍生物對神經母細胞瘤的細胞自噬作用之影響,結果顯示CA-4藥物及新型烯雙炔衍生物中LO-OMe、LO-NH2及CPC15a皆能誘導LC3-II與p62蛋白表現量上升,而HYH10f雖能提升LC3-II蛋白表現量,但其對p62蛋白表現量則有抑制效應。其餘新型烯雙炔衍生物於LC3-II及p62蛋白則無顯著影響。本研究之結果顯示新型CA-4烯雙炔衍生物依其修飾取代官能基之不同影響細胞自噬標幟蛋白LC3-II及p62蛋白表現作用各異,其對於細胞自噬作用效用之訊息機轉值得進一步加以探討,對其作用路徑之瞭解將有助於其在做為抗癌或治療神經退化性疾病藥物效用之評估。
Autophagy is a process to clear unwanted protein aggregates and damaged organelles for recycling cellular resources. It is a critical mechanism to maintain cellular homeostasis for cellular survival when facing environmental stress. Therefore, aberrant autophagy might lead to the diseases such as cancer, pathogen infection and neurodegenerative diseases. Autophagic proecess depends on the fusion of autophagosome with lysosome for the enzymatic degradation of its content. Previous reports indicated the involvement of microtubule in mediating the fusion of autophagosome with either lysosome or late endosome. Therefore, proper dynamic for microtubule formation is critical for autophagic process. Combretastatin A-4 (CA-4) is a useful nature product exhibits anticancer and anti-angiogenesis activity by targeting microtubule formation. However, its clinical use is limited as it exhibits drawbacks such as high toxicity and low water solubility. To improve its clinical use, efforts are ongoing in synthesizing better CA-4 derivatives as anticancer drug candidates. A series of Combretastatin A-4 (CA-4) enediyne derivatives were synthesized by Professor Ming-Jung Wu in the Department of Chemistry of National Sun Yat-Sen University. In this thesis, research was focusing on the analyzing their effects on the microtubule formation in neuroblastoma SHSY5Y and hepatoma Hep3B cell lines by confocal microscopic analysis. The results showed that like CA-4, among 9 enediyne derivatives analyzed, LO-OMe、LO-NH2、LO-py and HYH10f could inhibit microtubule formation using dosage of their individual IC50. The results of flow cytometric cell cycle analysis showed that LO-OMe、LO-NH2 and HYH10f also had antimitotic effect in that they caused G2/M arrest of SHSY5Y cells. Whereas, the derivatives CPC14c, CPC20a, CPC15a, CPC19a and HYH10a had no effects on microtubule formation or cell cycle arrest. These results indicated the modification or replacement of different function groups might affect their activities differentially. We further investigated the effects of these CA-4 enediyne derivatives on the autophagic process by monitoring the level of two autophagic marker proteins LC3-II and p62 using western blot analysis. Our results showed that like CA-4, LO-OMe, LO-NH2 and CPC15a could lead to the increase of both LC3-II and p62. Compound HYH10f could increase LC3-II level, but not on the level of p62. The rest of the derivative compounds had no effects on the level of both LC3-II and p62. Our results again showed that functional modification might affects autophagic process differentially. The detail signaling mediating their effects on autophagy awaits further investigation. Understanding the molecular mechanism underlies might be helpful in evaluation of their use as therapeutic agents for cancer or neurodegenerative diseases.
目錄
論文審定書 i
誌謝 ii
中文摘要 iv
Abstract vi
前言 1
研究動機 16
材料方法 17
結果 24
討論與總結 28
參考文獻 32
圖表 39
附錄 61
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107.陳佩婍, 設計與合成含烯雙炔結構之抗腫瘤藥物, in 國立中山大學化學系2011, 國立中山大學化學系.
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