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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳基旺(Ji-Wang Chern) | |
dc.contributor.author | Chiung-Hua Huang | en |
dc.contributor.author | 黃瓊嬅 | zh_TW |
dc.date.accessioned | 2021-06-08T04:28:57Z | - |
dc.date.copyright | 2010-03-12 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-01-25 | |
dc.identifier.citation | Chapter I
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22807 | - |
dc.description.abstract | 一般認為慢性發炎為癌症的傾向因子,但連結的精確機制則有待釐清。 CX9051為本實驗室確認之環氧酶-2(COX-2)及5-脂氧合酶(5-LOX)雙重抑制劑的苯駢[1.3.2]-1,1-雙氧雙噻唑偶極體衍生物,且顯示有抗發炎及抑制癌細胞增生的活性。本論文的結果證實,CX9051可以抑制脂多醣(LPS)引起的前列腺素E2 (PGE2)及腫瘤壞死因子α (TNF-α)生成,且可降低COX-2、iNOS、Akt及NF-κB蛋白質表現量及NF-κB核內外轉移。另外,CX9051可抑制前列腺癌細胞株的增生及誘發細胞凋亡,此效果被證實為是經由調控NF-κB腫瘤壞死因子及增加腫瘤相關細胞凋亡誘導配體(TRAIL)的過度表現,並活化可與粒線體引起的內在凋亡途徑有交互作用的外在凋亡訊息,進而造成癌細胞產生細胞凋亡反應。本研究中所證實CX9051具有抑制增生及抗發炎活性之結果,證明CX9051可作為抗發炎及化學預防抗癌的前導化合物。另外,此論文研究利用結構修飾原理設計一類新穎的第一型拓樸異構酶(Top I)抑制劑,其中最有效的Top I抑制劑,化合物26,為喹啉-4-酮衍生物,藉由降低Top I蛋白質表現及引起DNA單股斷裂,造成Top I毒性引起的細胞毒殺效果,進而對大腸腫瘤誘發老鼠模式也具有治療性的抗腫瘤活性效果。根據化合物26所表現的抑制Top I活性及在HT-29細胞株中誘發細胞凋亡及抑制腫瘤誘發活性等結果,提供另一前導化合物可用於發展新穎的Top I抑制劑來治療癌症。總之,本論文研究結果顯示苯駢[1.3.2]-1,1-雙氧雙噻唑偶極體及喹啉-4-酮衍生物可分別作為發展抗發炎及抗癌藥物發展的先導化合物。 | zh_TW |
dc.description.abstract | While chronic inflammation is widely believed to be a predisposing factor for cancer, the exact mechanisms linking these conditions have remained elusive. CX9051, a benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivative identified as a COX-2 and 5-LOX dual inhibitor in our laboratory, exhibited anti-inflammatory activity and anti-proliferation effects. Our results demonstrated that CX9051 suppressed the LPS-induced PGE2 production and TNF-α generation and attenuated the protein expression of COX-2, iNOS, Akt, and NF-κB as well as NF-κB translocation. Furthermore, CX9051 could inhibit the proliferation and induced apoptosis of prostate cancer cell lines. The effect has been shown to be mediated via the regulation of NF-κB, the induction of TRAIL and the activation of extrinsic apoptotic signaling, which cross-react the activation of mitochondria mediated intrinsic pathways, leading to the apoptosis of cancer cells. The anti-proliferation and anti-inflammatory activities of CX9051 revealed in this thesis provided a propelling evidence for CX9051 serving as a promising lead compound to provide anti- inflammatory and chemopreventive benefits. In addition, a scaffold modification approach has been employed to design a novel class of Top I inhibitor in this thesis. The most effective Top I inhibitor 26, a 3-substituted quinolin-4(1H)-one derivative, elicited its cytotoxic effects of Top I poison through Top I down-regulation, which paralleled the induction of DNA single-strand breaks and followed with curative anti-tumor activity against the colon carcinoma xenograft tumor model. According to the impressive Top I inhibitory activity, pro-apoptotic activity in HT-29 cells and in vivo xenograft inhibition activity exhibited by 26, this investigation has provided an alternative lead compound for the development of novel Top I inhibitor for the treatment of cancer. In conclusion, the results in this thesis suggested that benzo[1.3.2]dithiazolium ylide 1,1-dioxide and 3-substituted quinolin-4(1H)-one derivatives were promising leads for the development of anti-inflammatory drugs and anticancer agents, respectively. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:28:57Z (GMT). No. of bitstreams: 1 ntu-99-D93423004-1.pdf: 7304651 bytes, checksum: af62161a8413063a88b27c9138238f18 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | Acknowledgement i
Abstract (Chinese) ii Abstract (English) iii Abbreviations iv Contents viii List of Tables x List of Figures xi Chapter I Introduction 1. Epidemiology and pharmacoeconomics of cancer 1 2. Development of current chemotherapeutic agents 1 3. Cancer and inflammation 2 4. Rational design of this thesis 3 5. References 4 Chapter II CX9051, a Dual Inhibitor Against Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX), as a Potential Anti-Inflammatory Agent in Human THP-1 Macrophages 1. Introduction 7 2. Aim 10 3. Materials and methods 10 4. Results 16 5. Discussion 22 6. Summary 25 7. Perspectives 26 8. References 28 Chapter III Proapoptotic and Antiproliferative Potential of the Selective Cyclooxygenase-2 Inhibitor CX9051 in Human Prostate Cancer Cell Lines 1. Introduction 56 2. Aim 61 3. Materials and methods 61 4. Results 67 5. Discussion 73 6. Summary 77 7. Perspectives 78 8. References 79 Chapter IV Molecular Mechanisms and Cellular Determinants of Response to a Topoisomerase I Inhibitor, a Quinolone Derivative, in Colon Cancer Cell Lines 1. Introduction 110 2. Aim 113 3. Materials and methods 113 4. Results 117 5. Discussion 120 6. Summary 122 7. Perspectives 122 8. References 124 Chapter V 147 Conclusion 147 Chapter VI 149 Future works 149 References 150 Appendix 3.1 Materials A1 Curriculum vitae A29 List of Tables Chapter I Introduction Table I-1. Therapeutic mechanisms of action of anticancer drugs 6 Chapter II CX9051, a Dual Inhibitor Against Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX), as a Potential Anti-Inflammatory Agent in Human THP-1 Macrophages Table II-1. Screening for COX-2 inhibitors 38 Table II-2. TNF-α inhibitors currently FDA approved or in development 40 Chapter III Proapoptotic and Antiproliferative Potential of the Selective Cyclooxygenase-2 Inhibitor CX9051 in Human Prostate Cancer Cell Lines Table III-1. Comparison of CX9051 and celecoxib induced cell cytotoxicity in various cancer cell lines 88 Chapter IV Molecular Mechanisms and Cellular Determinants of Response to a Topoisomerase I Inhibitor, a Quinolone Derivative, in Colon Cancer Cell Lines Table IV-1. Chemival structures of 33 quinolone and naphthyridine derivatives 130 Table IV-2. In vitro SRB assay to test the effectiveness of 12 quinolone and naphthyridine derivatives against 12 cancer cell lines 131 List of Figures Chapter II CX9051, a Dual Inhibitor Against Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX), as a Potential Anti-Inflammatory Agent in Human THP-1 Macrophages Figure II-1. Schematic pathways of the arachidonic cascade 42 Figure II-2. Examples of COX-2 inhibitors 43 Figure II-3. General scheme representing the main metabolic pathways leading to arachidonic acid products involved in the inflammatory process 44 Figure II-4. Effect of COX inhibition on cholesterol efflux proteins and atheromatous foam cell transformation 45 Figure II-5. Chemical structures of rofecoxib and celecoxib 46 Figure II-6. Examples of small-molecule COX/LOX dual inhibitors 46 Figure II-7. Comparison of COX-1 and COX-2 47 Figure II-8. The benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivative, CX9051 48 Figure II-9. Morphology and cytotoxicity of CX9051 and its derivatives in PMA derived THP-1 macrophages 50 Figure II-10. Effect of CX9051 on COX-1, COX-2, 5-LOX, FLAP, TNF-α, IL-1β, and iNOS mRNA levels in human macrophages 51 Figure II-11. Effect of CX9051 on LPS-induced COX-2 protein expression and PGE2 production 52 Figure II-12. Effects of CX9051 and its derivatives on TNF-α production 53 Figure II-13. Effects of CX9051 on COX-2, iNOS, Akt, ERK, JNK, and p38 protein expression associated with anti-inflammatory effects 54 Figure II-14. Effect of CX9051 on NF-κB pathways 55 Chapter III Proapoptotic and Antiproliferative Potential of the Selective Cyclooxygenase-2 Inhibitor CX9051 in Human Prostate Cancer Cell Lines Figure III-1. The timeline of apoptosis research 89 Figure III-2. Survival and apoptosis pathways in cancer cells 90 Figure III-3. Target NF-κB in anticancer chemotherapy 91 Figure III-4. Schematic of signalling through the PI3K/AKT pathway 94 Figure III-5. Molecular mechanisms of celecoxib and its anticarcinogenic effects 95 Figure III-6. CX9051 inhibited the proliferation of PC-3 cells 97 Figure III-7. CX9051 induced accumulation of SubG1 in prostate cancer cells 99 Figure III-8. CX9051 induced apoptosis in prostate cancer cells. 100 Figure III-9. Effect of CX9051 on apoptosis-related proteins expression in PC-3 cells 102 Figure III-10. CX9051 activated caspases pathways 104 Figure III-11. CX9051 down-regulated Akt via a sequential inhibition of GSK-3β and NF-κB 106 Figure III-12. Effect of CX9051 on NF-κB p65 in PC-3 cells 107 Figure III-13. A schematic representation of the proposed mechanisms of action of CX9051 on PC-3 cells 109 Chapter IV Molecular Mechanisms and Cellular Determinants of Response to a Topoisomerase I Inhibitor, a Quinolone Derivative, in Colon Cancer Cell Lines Figure IV-1. Introduction to DNA topoisomerases 132 Figure IV-2. Chemical structures of Top I inhibitors 135 Figure IV-3. Compound generation by scaffold modification 138 Figure IV-4. Anti-proliferation effect of 26 against HT-29 cells 139 Figure IV-5. Effect of CPT and 26 on the catalytic activity of human DNA Top I 140 Figure IV-6. Effect of quinolone and naphthyridine derivatives on Top I-mediated DNA relaxation activity 141 Figure IV-7. Stimulation of Top I mediated DNA cleavage by 26 142 Figure IV-8. Quantification of cell cycle distribution of HT-29 cells by flow cytometry 143 Figure IV-9. Compound 26 induced chromosomal DNA strand breaks as revealed by comet assay 144 Figure IV-10. Molecular pathways involved in cellular responses to Top I cleavage complexes 145 | |
dc.language.iso | en | |
dc.title | 苯駢[1.3.2]-1,1-雙氧雙噻唑偶極體及喹啉-4-酮衍生物之分子及細胞機制研究 | zh_TW |
dc.title | Studies on Molecular and Cellular Mechanisms of Benzo[1.3.2]dithiazolium Ylide 1,1-Dioxide and Quinolin-4-one Derivatives | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 王光昭(Kuang-Chao Wang),李安榮(An-Rong Lee),顧記華(Jih-Hwa Guh),陳香惠(Grace Shiahuy Chen),忻凌偉(Ling-Wei Hsin),孔繁璐(Fan-Lu Kung),楊家榮(Chia-Ron Yang) | |
dc.subject.keyword | 環氧酶,-2,抗發炎,抑制增生,細胞凋亡,第一型拓樸異構酶, | zh_TW |
dc.subject.keyword | cyclooxygenase-2,anti-inflammation,anti-proliferation,apoptosis,topoisomerase I, | en |
dc.relation.page | 151 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2010-01-26 | |
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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