臺灣博碩士論文加值系統

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。

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.

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

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Chapter IV
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Chapter VI
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