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研究生:李長鴻
研究生(外文):Chang-Hung Li
論文名稱:利用MitomycinC和TNF-α及NF-κBInhibitor的複合式化學療法在MBT-2膀胱癌上的應用及相關機制
論文名稱(外文):Study on the application of using NF-κB inhibitor with Mitomycin C and TNF-α to promote cell death in MBT-2 bladder cancers
指導教授:唐世杰
指導教授(外文):Shye-Jye Tang
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:113
中文關鍵詞:絲裂黴素C腫瘤壞死因子αNF-κB抑制劑膀胱癌化學療法 (化療)週期素D1細胞週期
外文關鍵詞:Mitomycin C (MMC)Tumor necrosis factor α (TNF-α)NF-κB InhibitorMBT-2Bladder cancersChemotherapyCyclin D1Cell cycle
相關次數:
  • 被引用被引用:2
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  • 下載下載:42
  • 收藏至我的研究室書目清單書目收藏:0
Mitomycin C為膀胱癌臨床上最常使用的藥物,其作用機制為DNA的烷基化及自由基的產生如超氧化物和氫氧化物自由基所造成的DNA斷裂,使細胞無法轉錄、轉譯,進而造成細胞的死亡。TNF-α為巨噬細胞受到LPS刺激時釋放出來的細胞激素,研究顯示和IFN-γ同時存在時會造成MBT-2的大量死亡。為提升膀胱癌之治療效果,實驗中選擇Mitomycin C和TNF-α與NF-κB抑制劑之共同處理下,尋找可能治療膀胱癌的活性。

在MBT-2中利用NF-κB Inhibitor抑制NF-κB的活性,再處理Mitomycin C或TNF-α,發現NF-κB Inhibitor和Mitomycin C長時間的共同處理下對於MBT-2的毒殺效果比單獨處理NF-κB Inhibitor或Mitomycin C來得好,但是在短時間共同處理下則NF-κB Inhibitor對於Mitomycin C的毒殺效果則有抑制的現象。分析cyclin D1之表現,發現NF-κB抑制劑可抑制其表現,使得細胞週期停留在G1期,因此造成Mitomycin C對於MBT-2毒殺效果的減低。

有文獻指出,臨床上目前使用的BCG會造成膀胱癌附近的巨噬細胞大量釋放TNF-α和IFN-γ,造成膀胱癌的死亡,但是不論單獨處理TNF-α或者IFN-γ對於膀胱癌的毒殺效果則不顯著。在論文中利用NF-κB Inhibitor和TNF-α共同處理下會造成MBT-2的大量死亡,比單獨處理NF-κB Inhibitor或TNF-α所造成的細胞死亡來得顯著,這可能是因為NF-κB Inhibitor抑制了TNF-α誘導NF-κB pathway,使得TNF-α趨於走向caspase-dependent和JNK pathway,造成MBT-2的大量死亡。根據我們的實驗結果,NF-κB Inhibitor和TNF-α共同處理MBT-2所造成的細胞死亡,除了caspase-dependent也具有caspase-independent pathway。

研究顯示NF-κB對於腫瘤細胞的存活及抗藥性上,扮演著重要的角色,我們期望能以臨床上常用的治療藥物Mitomycin C共同處理NF-κB Inhibitor的複合式療法,除了減少腫瘤的復發率和提高膀胱癌病患五年存活率之外,更進一步能夠了解這些抗癌藥物和NF-κB在膀胱癌中所扮演的作用機制,在膀胱癌的藥物治療上提供一些開發新型藥物治療的參考方向。
Mitomycin C (MMC), DNA cross-linking agents, is used as in the cancer chemotherapy. Critical steps in cytotoxicity toward MMC involve DNA repair efficiency, inhibition of replication, cell-cycle checkpoints, regulation, and induction of apoptosis.

Tumor necrosis factor α (TNF-α) is release by the LPS-stimulated macrophage. In the previous studies, TNF-α added with interferon gamma (IFN-γ) is able to induce cell death in the MBT-2 bladder cancer cells. Our studies focus the promotion of cytotoxicity of MMC and TNF-α using the combination of NF-κB inhibitor in the MBT-2 bladder cancer cells.

While NF-κB inhibitor combined with MMC in long-term treatment it is able to induce MBT-2 death. In contrast, NF-κB inhibitor combined with MMC in short-term treatment may attenuate cytotoxicity of MMC. In terms of the particular roles in the arrest of the cell-cycle, critical steps in cytotoxicity of MMC to induce MBT-2 death are in the S and G2/M phase. Cyclin D1, an NF-κB-regulated gene, is required to transit G1 phase into S phase. Our results demonstrate that decrase of cytotoxicity by the treatment of MMC combined with NF-κB inhibitor result from NF-κB inhibition down-regulating the expression of cyclin D1.

Recent reports have indicated that treatment of Bacillus Calmette-Gu□rin (BCG) stimulates macrophages releasing TNF-α and IFN-γ to induce cell death in the adjacent bladder cancers. In our observation, treatment of TNF-α combined NF-κB inhibitor induces cell death but not by TNF-α only. In addition, we demonstrated that the caspase-dependent and –independent pathway were observed after the treatment of NF-κB inhibitor combined with TNF-α in the MBT-2 bladder cancer cells.

Many studies have indicated that NF-κB plays an important role in the survival of cancers and resistance of anti-cancer drugs. We expect to use NF-κB inhibitor and combined MMC or TNF-α to contribute new cancer chemotherapy.
謝誌………………………………………………………………………p.8
中文摘要………………………………………………………………p.10
英文摘要………………………………………………………………p.12
縮寫表…………………………………………………………………p.14
壹、 序論……………………………………………………………p.15
一、 膀胱癌………………………………………………………p.15
膀胱癌的種類…………………………………………………p.15
膀胱癌的致病機制……………………………………………p.16
膀胱癌的治療…………………………………………………p.18
1. 手術治療………………………………………………p.18
2. 藥物治療………………………………………………p.18
3. 放射線治療……………………………………………p.19
4. 治療結果………………………………………………p.19
二、 Nuclear factor-kappa B (NF-κB) ……………………………p.20
三、 Mitomycin C (MMC) ………………………………………p.21
四、 Cyclin D1……………………………………………………p.22
五、 Tumor necrosis factor (TNF-α) ……………………………p.23
六、 實驗源起……………………………………………………p.25
貳、 實驗材料………………………………………………………p.26
1. 細胞株 (Cell line) ……………………………………………p.26
2. 酵素 (Enzyme) ………………………………………………p.26
3. PCR primer……………………………………………………p.26
4. Kit………………………………………………………………p.27
5. Marker…………………………………………………………p.28
6. 抗體 (Antibody) ………………………………………………p.28
7. 細胞培養 (Cell culture) ………………………………………p.28
8. 化學藥劑 (Chemical) …………………………………………p.28
9. 儀器 (Instrument) ……………………………………………p.29
參、 研究方法………………………………………………………p.30
1. 細胞培養及冷凍………………………………………………p.30
冷凍細胞活化…………………………………………………p.30
細胞繼代培養…………………………………………………p.30
細胞冷凍保存…………………………………………………p.31
2. 細胞數測定 (MTS) ……………………………………………p.31
3. RNA萃取………………………………………………………p.32
4. 反轉錄反應 (Reverse Transcription, RT) ……………………p.33
5. 聚合酵素連鎖反應 (Polymerase Chain Reaction, PCR) ……p.34
6. Clonogenic assay (Colonies formation assay) …………………p.34
7. 細胞破碎………………………………………………………p.35
8. SDS-PAGE (Sodium dodecyl sulfate – polyacrylamide gel electrophoresis) ………………………………………………p.35
9. 西方點墨法 (Western blotting) ………………………………p.38
10. 質體DNA的轉染 (Lipofectamine transient transfection) …p.39
11. Luciferase活性測定…………………………………………p.39
12. Apoptosis Assay (APOPercentageTM) ………………………p.39
13. Cell Proliferation Analysis (BrdU Assay) ……………………p.40
14. Cell Cycle Analysis (Propidium Iodide Assay) ………………p.41
肆、 研究結果………………………………………………………p.42
1. NF-κB inhibitor在MBT-2上對於調控細胞週期的影響……p.42
(1) NF-κB inhibitor抑制MBT-2的生長……………………p.42
(2) NF-κB inhibitor使細胞的細胞週期停在G1期…………p.42
(3) NF-κB inhibitor藉由抑制NF-κB達到抑制細胞週期從G1期進入到S期的效果……………………………………p.43
(4) NF-κB inhibitor抑制MBT-2細胞株中cyclin D1的基因轉錄…………………………………………………………p.45
(5) 大量表現cyclin D1可恢復NF-κB inhibitor造成的細胞週期抑制現象及Mitomycin C的毒殺效果…………………p.45
2. NF-κB inhibitor和Mitomycin C對於MBT-2的探討…………p.46
(1) NF-κB inhibitor和Mitomycin C在長時間的處理下對於MBT-2的死亡有加成的效果……………………………p.46
(2) NF-κB inhibitor和Mitomycin C在短時間的處理下對於MBT-2的死亡有抑制效果………………………………p.47
(3) 在MBT-2中Mitomycin C對細胞的毒殺作用可能是啟動了caspase-9細胞凋亡路徑…………………………………p.47
3. TNF-α在MBT-2細胞株中造成細胞凋亡的機制探討………p.48
(1) TNF-α造成MBT-2細胞株的死亡並不會隨著時間的增長而增加………………………………………………………p.48
(2) TNF-α造成MBT-2死亡路徑為caspase-dependent……p.49
(3) MBT-2對於TNF-α有60% 抗藥性……………………p.49
4. NF-κB inhibitor和TNF-α共同處理MBT-2細胞株之探討…p.49
(1) NF-κB inhibitor和TNF-α共同處理會造成MBT-2的大量死亡…………………………………………………………p.50
(2) NF-κB inhibitor引起的細胞凋亡路徑不同於TNF-α的caspase-dependent路徑…………………………………p.50
伍、 討論……………………………………………………………p.51
一、 NF-κB inhibitor 24小時內抑制Mitomycin C的毒殺效果可能是藉由間接抑制cyclin D1將細胞的細胞週期抑制在G1期……………………………………………………………p.51
二、 NF-κB inhibitor和Mitomycin C共同處理下將細胞週期抑制在G1期,並在隨後造成細胞進一步的死亡………………p.52
三、 MBT-2可能為cyclin D1過度表現的細胞株………………p.53
四、 NF-κB inhibitor和Mitomycin C在臨床上可能的新的複合式療法…………………………………………………………p.54
五、 TNF-α造成細胞resistant之機制…………………………p.55
六、 TNF-α和NF-κB inhibitor造成細胞大量死亡之機制可能合併caspase-dependent和-independent之途徑…………………p.56
七、 NF-κB inhibitor可能的化學藥劑副作用 (chemical inhibitor side effect) …………………………………………………p.56
陸、 參考文獻………………………………………………………p.58
柒、 附圖……………………………………………………………p.75
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