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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁博煌(Po-Huang Liang) | |
| dc.contributor.author | En Ning Lui | en |
| dc.contributor.author | 雷恩寧 | zh_TW |
| dc.date.accessioned | 2021-06-16T09:23:51Z | - |
| dc.date.available | 2020-06-21 | |
| dc.date.copyright | 2017-07-12 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-06-21 | |
| dc.identifier.citation | REFERENCE
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59441 | - |
| dc.description.abstract | 先前我們發現I-Lys可藉由iodomethyl ketone來烷基化caspase-7 (CASP7)上的Cys246，從而阻止CASP7與X-linked inhibitor of apoptosis protein (XIAP) 的蛋白-蛋白交互作用(PPI)並釋放活化的CASP7，進而有選擇性地殺死具CASP7:XIAP蛋白複體累積的癌細胞，其通常為CASP3表現量低(CASP3/DR)的癌細胞 [1]. 因CASP3表現量減低使得細胞凋亡也減少，從而讓癌細胞產生抗藥性。I-Lys提供了一個有效且安全的治療方法，因正常細胞無CASP7:XIAP蛋白質複體。除不可逆I-Lys，之前我們實驗室的博士畢業生陳世勳透過電腦模擬從Sigma化合物庫找到一個可逆的抑制劑，643943。本篇論文旨在測試I-Lys及643943的類似物對於毒殺MCF-7乳癌細胞的結構-功能關係及引發癌細胞凋亡的機制。我們發現較弱的離去基會減弱I-Lys類似物的活性而保護基影響不大。643943與 Staurosporine (STS) 的結合對於殺死具有Taxol抗性的MCF-7乳癌細胞(7TR)有加成作用。我們發現643943的類似物-0909所引發的細胞凋亡機制與643943不同，乃通過MAPK來調控細胞凋亡，並且活化許多caspases，而643943 主要活化CASP7。我們的研究提供了一個對於CASP3表現量低和抗藥性癌細胞的治療方法。 | zh_TW |
| dc.description.abstract | Previously, we demonstrated that disruption of protein-protein interaction (PPI) of caspase-7 (CASP7) and X-linked inhibitor of apoptosis protein (XIAP) by using I-Lys with an iodomethyl ketone warhead to alkylate Cys246 of CASP7, selectively killed cancer cells with accumulation of CASP7:XIAP complexes, which are caspase-3 down-regulated (CASP3/DR) [1]. CASP3/DR frequently confers resistance to cancer therapy due to reduced apoptotic machinery. This represents an effective and safe strategy for chemotherapy because the CASP7:XIAP complexes are not accumulated in normal cells. Unlike the I-Lys irreversible PPI inhibitor, through compute virtual screening, a reversible PPI inhibitor, 643943, a compound from Sigma compound bank was discovered by Chen, S. H. et al. In this thesis, I aimed to determine the structure-activity relationship of the I-Lys and 643943 analogues and the induced apoptotic mechanisms. We found that in I-Lys analogues, the weaker leaving group reduced the activity, but C-terminal protecting groups did not affect so much. We also found synergistic effect of 643943 combining STS in killing 7-TR, a Taxol-resistant MCF-7 cells. The analogue 0909 adopts different mechanism to induce apoptosis in MCF-7 cells through MAPK family to activate various caspases, unlike 643943 that mainly activated CASP7. Our studies demonstrated a promising therapeutic strategy against CASP3/DR and multidrug resistant cancers. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T09:23:51Z (GMT). No. of bitstreams: 1 ntu-106-R04b46001-1.pdf: 2905372 bytes, checksum: 2532ffe50763bc17fa0fa316ad3677f3 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | TABLE of CONTENTS
中文摘要 iv ABSTRACT v ABBREVIATIONS vi (1) INTRODUCTION 1 1.1 Breast cancer 1 1.2 Chemoresistant in breast cancer 2 1.3 Caspase-3 3 1.4 Caspase-7 3 1.5 XIAP 4 1.6 Apoptosis 6 1.6.1 Intrinsic apoptosis pathway 6 1.6.2 Extrinsic apoptosis pathway 7 1.7 MAPK signaling pathway 8 1.7.1 ERK pathway 9 1.7.2 c-JUN N-terminal kinase (JNK) pathway 9 1.7.3 p38 pathway 10 1.8 Previous studies and the present work 11 (2) MATERIALS AND METHODS 14 2.1 Chemicals 14 2.2 Cell culture and cell lines 14 2.3 Western blot 15 2.4 Determination of caspase activities 16 2.5 MTT assay 16 2.6 PI-based flow cytometry analysis 17 2.7 Generation of paclitaxel-resistant cell line 17 (3) RESULTS 19 3.1 SAR of I-Lys analogues in killing MCF-7 versus MCF-10A 19 3.2. SAR of 643943 and its analogues in killing MCF-7 versus MCF-10A 20 3.3 Activation of CASP7 by the active compounds in MCF-7 cells 23 3.4 643943 effectively killed different CASP3/DR cell lines 24 3.5 Synergistic effect of 643943 with Staurosporine (STS) in killing MCF-7/TR 25 3.6 AC77, 0909, and 643943 were selected for further studies 25 3.7 The CASP7-mediated apoptotic signaling pathway triggered by the selected compounds 26 3.8 Synergistic effect of 643943 and 0909 27 3.9 0909 upregulated pro-apoptotic proteins and inhibited the anti-apoptotic proteins. 28 3.10 0909-induced apoptosis was mediate through the activation of p38 and JNK MAPK pathways 28 (4) DISCUSSIONS 30 REFERENCE 34 TABLE 39 FIGURE 40 | |
| dc.language.iso | en | |
| dc.subject | 蛋白抑製劑 | zh_TW |
| dc.subject | 乳癌細胞 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | MCF-7 | en |
| dc.subject | protein-protein inhibitor | en |
| dc.subject | apoptosis | en |
| dc.title | 探討抑製劑的結構改變如何影響CASP7:XIAP 之間的相互作用並選擇性地殺死CASP3表現量低的癌細胞與具有抗藥性癌細胞 | zh_TW |
| dc.title | Structure-activity relationship of CASP7:XIAP inhibitors for selectively killing CASP3/DR and drug-resistant malignancies | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 余榮熾(Lung-Chih Yu),張茂山(Mau-Sun Chang) | |
| dc.subject.keyword | 乳癌細胞,細胞凋亡,蛋白抑製劑, | zh_TW |
| dc.subject.keyword | MCF-7,apoptosis,protein-protein inhibitor, | en |
| dc.relation.page | 65 | |
| dc.identifier.doi | 10.6342/NTU201701016 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-06-21 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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