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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25489完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊泮池 | |
| dc.contributor.author | Ting-Rong Chern | en |
| dc.contributor.author | 陳庭榕 | zh_TW |
| dc.date.accessioned | 2021-06-08T06:15:33Z | - |
| dc.date.copyright | 2007-02-13 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-01-30 | |
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Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. J Cell Biol 2001, 153, 999-1010. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25489 | - |
| dc.description.abstract | 本論文主旨為探討苯磺醯胺衍生物J-3944對非小型細胞肺癌細胞A549之抗癌活性機轉。本實驗室所設計合成之benzenesulfonamidoindolinone類衍生物，最初目的為設計CDK2抑制劑作為抗癌化合物，然而，其抑制細胞生長的活性大於其抑制CDK2的活性，因此推測其抑制癌細胞生長的活性除對CDK2之抑制外，另有其它的機制。本論文進而研究其抗癌機制，J-3944對於各種腫瘤細胞均有不錯的生長抑制活性，其中以對A549細胞之效果最好(GI50 = 0.07μM)，流式細胞儀分析發現J-3944 會使A549 細胞停滯在G2/M 時期，TUNEL 實驗顯示細胞凋亡現象。經由共軛焦顯微鏡觀察到細胞於J-3944 的作用下呈現類似colchicine 的短而內聚的微小管形態。體外微小管聚合實驗及競爭結合colchicine 結合位置實驗顯示J-3944 會結合於colchicine 結合位置並抑制微小管的聚合。西方點墨法觀察發現，細胞週期相關蛋白MPM2、cyclin B1 的表現量在3 - 12 小時增加，造成M 時期的停滯。但在18 小時後MPM2 的表現量消失，顯示細胞有mitotic slippage 的現象並成為tetraploid 形態的細胞。而A549 細胞在J-3944 的作用下，p53 的表現量亦有大量增加的現象，調控之Bcl-2 家族中促凋亡蛋白PUMA、Bad、Bax 因受p53 誘導而表現量增加，同時，抑凋蛋白Mcl-1 也有減少的現象。這些變化促使粒線體通透性改變而釋放出cytochrom c，進一步活化caspase-3、9 而導致內生性路徑之細胞凋亡。Survivin 則扮演著兩種角色，在有絲分裂停滯時期表現量上升，與參與紡綞體形成之調控有關，在mitotic slippage 之後，其表現量則下降可促進細胞凋亡的進行。Cathepsin B 的裂解活化型式亦有增加，可能參與細胞凋亡的進行。 | zh_TW |
| dc.description.abstract | The aim of this thesis is to investigate the anticancer mechanism of J-3944, benzenesulfonamide, against the non-small cell lung cancer A549. J-3944 is a benzenesulfonamidoindolinone, a small molecule designed and synthesized in our laboratory as an anticancer agent. It is origionally designed as a CDK2 inhibitor for anticancer agents. However, it was found that the inhibitory growth activity of cancer cells was much more pronounced than its enzymatic activity against CDK2, indicative of other mechanisms involved for the inhibitory activity aside from the CDK2 inhibitory activity. Further investigation by this research revealed that J-3944 exhibited potent inhibitory activity against various human cancer cell lines, especially the invasive human lung cancer A549 cell line (GI50 = 0.07 μM). The flow cytometric cell cycle analysis of J-3944 on A549 cell lines showed G2/M arrest. The TUNEL assay confirmed an apoptosis. The confocol microsope showed that J-3944 resulted in shorter microtubule scatter around necleous in A549 cell. The microtubule assembly assay and tubulin competition-binding SPA assay revealed J-3944 as a microtubule inhibitor and through binding to the colchicines binding site. Results of Western blotting showed an increased expression of some mitotic marker protein like MPM-2 and cyclin B1 during 3 to 12 hr indicating that cells entered and blocked at mitotic phase. The expression of p53 was significantly increased after treatment. The pro-apoptotic proteins of Bcl-2 family, PUMA、Bad、Bax, were induced by p53. Meanwhile, the expression of anti-apoptotic protein of Bcl-2 family: Mcl-1 was decreased. The net-effenct of thoese Bcl-2 family proteins caused mitochondrial outer membrane permeabilization and subcequently the release of cytochrome c. Furhter, the activation of caspase-3 and 9 triggered apoptosis. Survivin played a dual role in up-regulated when cell arrested at M phase because it participated in the spindle formation and down-regulated following mitotic arrest indicating its IAPs function. We also found that increased expression of active cleaved form of cathepsin B might be involved in apoptosis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T06:15:33Z (GMT). No. of bitstreams: 1 ntu-96-R93423026-1.pdf: 1426865 bytes, checksum: 3a91e36dfadd0763833939d574779c94 (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 中文摘要 i
英文摘要 ii 第一章 緒論 1 1.1 研究背景 1 1.2 文獻回顧 2 1.2.1 抗微小管藥物與癌症的治療 2 1.2.2 細胞死亡 3 1.2.3 影響細胞凋亡相關調控因子 4 第二章 實驗材料與方法 8 2.1 實驗材料 8 2.2 培養液的製備 9 2.3 解凍細胞、細胞繼代與培養 9 2.4 Sulforhodamine B (SRB) assay 10 2.5 細胞總量蛋白質的萃取 11 2.6 分離Mitochondria/Cytosol蛋白質 11 2.7 西方墨點法 12 2.8 TUNEL檢測法偵測細胞凋亡 13 2.9 共軛焦顯微鏡螢光染色法 14 2.10 流式細胞儀測定細胞週期及細胞凋亡 14 2.11 In Vitro 微小管聚合實驗 15 2.12 Colchicine及Tubulin Competition-Binding SPA 15 2.13 Caspase活性分析 15 第三章 結果 17 3.1 J-3944對人類癌症細胞株生長抑制效果 17 3.2 J-3944對人類肺癌細胞A549生長週期的影響 17 3.3 J-3944誘導人類肺癌細胞A549進行DNA斷裂 18 3.4 J-3944對體外微小管聚合的影響 18 3.5 J-3944對微小管Colchicine結合位置的影響 19 3.6 J-3944對人類肺癌細胞A549的微小管形態之影響 19 3.7 J-3944對人類肺癌細胞A549細胞週期相關蛋白的影響 20 3.8 J-3944對人類肺癌細胞A549的p53及其相關蛋白之影響 20 3.9 J-3944對人類肺癌細胞A549之Bcl-2 family蛋白影響 21 3.10 J-3944引起人類肺癌細胞A549粒線體cytochrome c和AIF釋放 21 3.11 J-3944對人類肺癌細胞A549中caspase活性之影響 22 3.12 J-3944對人類肺癌細胞A549的IAPs蛋白表現影響 22 3.13 J-3944對人類肺癌細胞A549外生性細胞凋亡路徑影響 23 3.14 J-3944對人類肺癌細胞A549的Cathepsins影響 23 第四章 討論 24 4.1 J-3944對腫瘤細胞之生長抑制效果 24 4.2 J-3944使A549細胞進入Mitotic Arrest 25 4.3 J-3944引發A549細胞進行細胞凋亡 26 4.4 J-3944引發A549細胞p53表現量上升 26 4.5 J-3944引發A549細胞內生性細胞凋亡路徑 28 4.6 J-3944對Survivin的調控 30 4.7 J-3944引發A549細胞Cathepsin B的活化 31 第五章 結論 33 參考文獻 55 | |
| dc.language.iso | zh-TW | |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | 微小管 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | p53 | zh_TW |
| dc.subject | lung cancer | en |
| dc.subject | p53 | en |
| dc.subject | apoptosis | en |
| dc.subject | microtubule | en |
| dc.title | Benzenesulfonamidoindolinone衍生物J-3944對人類非小細胞肺癌細胞A549抗癌活性機轉研究 | zh_TW |
| dc.title | Mechanistic Studies of Benzenesulfonamidoindolinone Derivative J-3944 against Human Non-small Cell Lung Cancer A549 Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顧記華,陳香惠,忻凌偉,孔繁璐 | |
| dc.subject.keyword | 微小管,細胞凋亡,p53,肺癌, | zh_TW |
| dc.subject.keyword | microtubule,apoptosis,p53,lung cancer, | en |
| dc.relation.page | 61 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2007-01-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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