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研究生:杜蘭君
研究生(外文):Tu Lan-Chun
論文名稱:Mana-Hox抑制細胞生長的作用機制探討
論文名稱(外文):The action mechanisms of Mana-Hox in the inhibition of cultured cancer cell growth
指導教授:葉小帆葉小帆引用關係
指導教授(外文):Yeh Sheau-Farn
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:214
中文關鍵詞:細胞毒性有絲分裂期中心體微管蛋白核酸抗癌藥前導化合物
外文關鍵詞:cytotoxicityG2/M phasecentrosomemicrotubuleDNAanticancer druglead compound
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無法長期使用、好發的副作用、及抗藥性,限制了化療藥物治療癌症的臨床用途。為了解決這些問題,許多研究人員致力於開發具有新的作用機制、或新的標的物的抗癌藥。而自然界為開發新藥提供了豐富的資源。除了本身的活性,天然物也為小分子藥物的合成,提供了各式各樣的結構模板。Manzamines是b-carboline 生物鹼,萃取自海綿Haliclona sp. ,對人類腫瘤細胞有強烈的細胞毒性,但作用機制不明。本論文針對一系列合成的manzamines衍生物,試圖尋找新的活性化合物,並探討其作用機制。
研究中發現,Mana-Hox (化合物1) 對幾種癌細胞株有細胞毒性,IC50介於1-6 mM之間。由細胞週期分析的結果得知,肝癌細胞HepG2/A2經0.8 mM Mana-Hox處理24小時,細胞週期累積在G2/M期的現象,先將細胞週期同步化之後,則發現這種G2/M期累積是暫時性的,Mana-Hox延後細胞脫離M期不是永久性的停滯。依間接免疫螢光染色實驗的結果,說明了造成這個現象的原因是Mana-Hox破壞了正常有絲分裂的機制;誘導異常紡錘體出現,例如三極和四極紡錘體且紊亂染色體排列,因而減低細胞存活率。以中心體標記蛋白 g tubulin、 Aik、和NuMA分析微管蛋白構成中心時發現,所有的端點都有這些標記蛋白。此外,群落分析的結果則證明,Mana-Hox所造成的M期效應與它所造成的細胞死亡有關。
在細胞內聚合分析中,Mana-Hox不影響微管蛋白形成,以純化的微管蛋白單元,評估Mana-Hox對聚合反應的作用則發現,Mana-Hox也沒有促進微管蛋白聚合的能力。可是對於中心體nucleation,會誘導異常的星狀體形成。這表示中心體是Mana-Hox的標的物之一。
各種光譜分析的結果發現,Mana-Hox有結合DNA的能力(Ki, 32.1x106 M-1),能夠取代ethidium bromide (Ki, 17.8x106 M-1) 和Hoechst 33258 (Ki, 1.46x106 M-1),C50分別為10 mM和2.5 mM。分子模擬呈現Mana-Hox分別以嵌入或由小凹溝結合DNA時的構形,結合的最低能量分別為-16 kcal/mol和-186 kcal/mol。但gel shift assay的結果也證明Mana-Hox可以嵌入DNA。所以可能是以小凹溝結合伴隨嵌入的模式與DNA結合。Plasmid relaxaion分析的結果,說明了Mana-Hox對calf thymus toptisomerase I完全沒有作用,但在極高濃度50 mM有抑制topoisomerase II relaxation的作用,可能是因為結合DNA造成的。
由螢光顯微鏡直接觀察的結果發現,Mana-Hox能夠快速的進入細胞 (約1分鐘),並停留在細胞中一段時間 (4 天),正說明其產生持續藥效的原因,但細胞內螢光最強的時間發生在M期效應之前。
論文中也以細胞毒性及DNA結合能力,比較其他Mana-Hox相似物的活性。研究結果發現,細胞毒性與結構變化沒有直接關係,就DNA結合能力而言,帶有carbazole取代基的衍生物,有DNA結合能力,且與烷基鏈長成負相關,最適長度為2-5個碳;b-carboline pyridine環的飽和度,dihydro-b-carboline (化合物1-3, 8, 9, 14, 15, 20, 21) 的結合能力比tetradydro-b-carboline (化合物14, 15, 20, 21) 的好。Mana-Hox是唯一造成M期效應的化合物,也是其中活性較佳的。
綜合所有的實驗結果證明,Mana-Hox以其獨特的作用方式,造成腫瘤細胞死亡。因干擾中心體和染色體的構成,而破壞有絲分裂機制,延後細胞脫離M期。中心體和染色體仍是Mana-Hox最有可能的細胞內標的物;雖然真正的影響尚需釐清。Mana-Hox是DNA結合劑,可以嵌入或由小凹溝結合模式與DNA結合;分子模擬也說明此結果。但並不會因此而抑制topoisomerase。DNA結合能力受carbazole上烷基取代基及b-carboline上質子供應基的影響,可能是因為氫鍵形成影響了藥物DNA複合物的安定性;但目前的研究結果,無法說明細胞毒性與結構間的關係。這個研究結果預期,Mana-Hox將成為未來開發抗癌藥的前導化合物。

Clinical used cancer chemotherapeutic agents remain have clear limitations, including durable antitumor efficacy, general toxicities, and resistances. To resolve these problems, a great deal of effort has been expended in the development of new anticancer agents with novel mode of action or directed at a specific target. Nature is a rich source for searching novel anticancer agents, natural products act not only as active compounds but also provide diverse structural template for synthesis of small molecules. Manzamines are b-carboline alkaloids, isolated from a marine sponge Haliclona sp., with potent cytoxicity against human tumor cells, however, the mode of action remains unclear. In this study, a series of synthetic derivatives of manzamines were used to search new active compounds and to explore the mechanisms of action.
Mana-Hox (compound 1) was shown to exhibit cytotoxicity against various tumor cell lines with the IC50 range from 1 to 6 mM. Flow cytometric analysis showed that Mana-Hox (0.8 mM at 24 h) partially arrested human hepatoma HepG2/A2 cells at the G2/M phase. When cell cycle synchronization was performed before drug treatment, Mana-Hox caused G2/M accumulation resulting from a delayed M phase progression rather than direct mitotic arrest. When examined by immunofluorescence staining for tubulin, Mana-Hox caused aberrant spindles, such as tripolar- and quadripolar spindles, in the mitotic cells. The increased number of spindle poles was associated with chromosomes displacement from the metaphase plate. Analysis of microtubule organizing centers (MTOC) with centrosome markers, g tubulin, Aik, and NuMA, indicated that was localized to all poles of multipolar spindles. These results indicated that Mana-Hox impaired the mitotic apparatus, disorganized the chromosomes, and thus resulted in cell death. Colony formation assay revealed that the mitotic arrested cells had lost their ability to grow.
Cellular polymerization assay showed that Mana-Hox did not change microtubule polymer mass. The effects of Mana-Hox on the polymerization of purified tubulin, using turbidity assay to evaluate the extent of microtubule polymerization, Mana-Hox had little effects on the polymerization of microtubule. However, the nucleation function of purified centrosomes was altered, abnormal asters formed in the presence of Mana-Hox, suggested that centrosome was one of the targets of Mana-Hox.
Absorption, fluorescence, and circular dichroism spectrum analysis demonstrated that Mana-Hox (Ki, 32.1x106 M-1) was a DNA binder. It displaced ethidium bromide (Ki, 17.8x106 M-1) and Hoechst 33258 (Ki, 1.46x106 M-1) from calf thymus DNA with C50 values at 10 mM and 2.5 mM, respectively. Gel shift assay indicated that Mana-Hox was a DNA intercalating agent, which retarded the electrophoretic mobility of various types of DNA. Molecular modeling was performed to delineate the binding conformations of Mana-Hox-DNA interaction either by intercalation or by minor groove binding. The estimated binding energy values of these two interaction forms were —16 kcal/mol and —186 kcal/mol, respectively. These data suggested that Mana-Hox binds to DNA by a mixing mode, intercalation or minor groove binding or both. Moreover, the effects of the Mana-Hox on DNA cleavage by calf thymus DNA topoisomerases I and II were investigated. Plasmid relaxation assays using supercoiled DNA showed that Mana-Hox had no effect on topoisomerase I activity in vitro, whereas very high concentrations (50 mM) of Mana-Hox inhibited topoisomerase II activity.
Fluorescence microscopic study showed that Mana-Hox entered cells very rapidly (about 1 min) and accumulated in intracellular compartments such as endoplasmic reticulum, mitochondria, and nuclear envelop for a long time (4 days) and thus produced persistent drug effects. The flow cytometry analysis showed that the maximum intracellular fluorescence occurred prior to M phase block.
The present report compared the effects of the differing Mana-Hox analogs on cyotoxicity and DNA binding ability. There was no correlation between cytotoxicity and structures. Mana-Hox was the best among all the analogs and was the only one to induce M phase effects. Their capability to bind to DNA was investigated by spectroscopic techniques and gel mobility shift assay. The analogs containing carbazole substitution displayed much better DNA binding ability, however, the negative correlation were present between the alkyl chain length and the DNA binding ability. The optimal chain length is 2 to 5 carbon. In addition, dihydro-b-carboline analogs (compound 1-3, 8, 9, 14, 15, 20, 21) were better than tetrahydro-b-carboline (compound 14, 15, 20, 21).
In conclusion, this study demonstrated that Mana-Hox caused cell death of cultured cancer cells by a novel mode of action. It impaired the mitotic apparatus by interfering centrosome and chromosome organization, and thus delayed cells exit from M phase. Although the precise effects of Mana-Hox on centrosome and intracellular DNA require clarification, centrosome and DNA remains the talented target. Mana-Hox showed to act as a DNA binder either by intercalation or by minor groove binding mode. Molecular modeling further illuminated these results. But it seems unlikely that topoisomerase is the target of Mana-Hox. The DNA binding capacity was influenced by the alkyl substitution on carbazole chormophore and proton donor on b-carboline chromophore, seems to be due to hydrogen bond formation resulting in stable drug-DNA complex. However, this study could not provide information between structure and cytotoxicity. The prospect that Mana-Hox acts as a lead compound in future develops anticancer agents.

封面
縮寫表
英文摘要
中文摘要
壹、緒論
1.1 細胞分裂機制
1-1-1 紡錘體
1-1-2 中心體週期
1.2 細胞週期的調控
1-2-1 Cell cycle engine
1-2-2 Cell cycle brake
1.3 抗癌藥分類
1.4 以天然物為新藥開發的來源
貳、材料及方法
2.1 儀器
2.2 材料
2.3 方法
參、結果
3.1 Mana-Hox的生物活性
3.1-1 Mana-Hox的細胞毒性
3.1-1.1 Mana-Hox有不可逆的毒殺效應
3.1-2 Mana-Hox對生長調控蛋白的作用
3.1-3 Mana-Hox對細胞週期的影響-M期暫停效應
3.1-3.1 未同步化細胞
3.1-3.2 同步化細胞
3.1-4 細胞週期影響細胞對Mana-Hox的感受性
3.1-5 Mana-Hox引起的M期暫停效應有持續性
3.1-6 Mana-Hox引起的M期暫停效應與其細包毒性有關
3.1-7Mana-Hox干擾有絲分裂機制
3.1-7.1 Mana-Hox造成細胞暫停在metaphase-like stage
3.1-7-2 Mana-Hox增加紡錘端點的數量
3.1-7.3 Mana-Hox不影響其他相關核蛋白的分佈
3.1-8 Mana-Hox活化紡錘檢查點
3.1-9 Mana-Hox干擾細胞分裂的機制具有持續性
3.2 Mana-Hox標的物
3.2-1 Mana-Hox對微管蛋白的作用
3.2-2 Mana-Hox對中心體的作用
3.2-3 Mana-Hox對DNA的作用
3.2-3-1 Mana-Hox是DNA結合劑
3.2-3.2 Mana-Hox與DNA結合的方式
3.2-3.3 Mana-Hox對topoisomerase的活性抑制作用
3.2-3.4 Mana-Hox與細胞內DNA的作用
3.2-4 Mana-Hox在細胞內的分佈
3.3 結構活性相關分析
3.3-1 Mana-Hox衍生物的細胞毒性
3.3-2 Mana-Hox衍生物的光譜特性
3.3-3 Mana-Hox衍生物結合DNA的能力
肆、討論
5.1 Mana-Hox細包毒殺作用的探討
5.2 Mana-Hox對細胞週期作用的探討
5.3 Mana-Hox對有絲分裂機制的探討
5.4 Mana-Hox活化紡錘體檢查點的探討
5.5 Mana-Hox造成的細胞死亡的探討
5.6 Mana-Hox與DNA的作用機制探討
5.7 Mana-Hox與細胞內DNA作用的探討
5.8 結構活性相關的探討
伍、結論
陸、參考文獻
附表

附圖

陸、參考文獻
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