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국회도서관 홈으로 정보검색 소장정보 검색
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결과 내 검색 동의어 포함

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Title Page

Contents

Abstract 7

Abbreviations 14

I. INTRODUCTION 16

1. Epothilones 16

2. Epothilones and colon cancer cell growth 20

2-1. Colon cancer cell growth 20

2-2. Microtuble disruption and colon cancer cell growth 22

2-3. NF-κB and cancer cell growth 25

3. Atherosclerosis and neointimal hyperplasia 28

3-1. Neointimal hyperplasia 28

3-2. Mechanism of neointimal hyperplasia 29

4. Objectives 33

II. MATERIALS AND METHODS 35

1. Materials 35

2. Cell culture 36

3. Cell proliferation assay 37

4. Western blot analysis 38

5. Gel electromobility shift assay 39

6. In vitro kinase assays 40

7. Transfection and luciferase activities assay 41

8. Tubulin polymerization assay 43

9. Immunofluorescent assay 43

10. TUNEL Assay 44

11. Flow Cytometry analysis 46

12. Carotid artery injury model 46

13. Morphometric analysis 47

14. Immunohistochemical analysis 48

15. siRNA assay 49

16. Statistical analysis 49

III. RESULTS 50

1. Effect of epothilones on the proliferation of colon cancer cell 50

1-1. Effect of epothilones on the proliferation of SW620 54

1-2. Effect of epothilones on the proliferation of cell cycle progression of SW620 56

1-3. Effect of epothilones on the apoptosis of SW620 59

1-4. Effect of epothilones on the activation of NF-κB in SW620 61

1-5. Effect of epothilones on the activation of IKK in SW620 66

1-6. Effect of epothilones on the polymerization of microtubule in SW620 72

1-7. Effect of epothilones on the expression of apoptotic cell death regulatory proteins in SW620 77

2. Effect of epothilones on the proliferation of rat aortic smooth muscle cell 81

2-1. Effect of epothilones on the proliferation of VSMC 85

2-2. Effect of epothilones on the apoptosis of VSMC 89

2-3. Effect of epothilones on the nuclear accumulation of p53 in VSMCs 94

2-4. Effect of pifithrin-α or p53 siRNA on the expression and translocation into nucleus of p53 97

2-5. Effect of epothilones on the apoptosis of VSMC as well as activation of p53 and caspase-3 in the neointimal hyperplasia region 102

IV. DISCUSSION 107

V. REFERENCES 121

VI. SUMMARY IN KOREAN 143

LIST OF TABLE

Table 1. Effect of EPOs on VSMC cell cycle progression. 93

LIST OF FIGURES

Fig. 1. Structures of the epothilones. 19

Fig. 2. Polymerization of tublin. 24

Fig. 3. Regulation of the cell cycle. 27

Fig. 4. Response of blood vessel as a complication of a reconstruction procedure or endarterectomy. 32

Fig. 5. Effect of epothilones on the cell viabilities of SW620 human colon cancer. 55

Fig. 6. Effect of epothilones on the cell cycle progression. 57

Fig. 7. Morphological changes and apoptotic cell death of SW620 treated with epothilones. 60

Fig. 8. Effects of epothilones on NF-κB activation in SW620 determined by gel mobility shift assay. 63

Fig. 9. Effect of epothilone on the NF-κB in SW620 cells determined by confocal microscope. 64

Fig. 10. Effect of epothilones on the IKK activation. 67

Fig. 11. Effect of IKK inhibitor and mutant IKKs on the epothilone-induced cell growth inhibition. 69

Fig. 12. Effect of IKK inhibitor and mutant IKKs on the epothilone-induced NF-κB (p50) translocation. 70

Fig. 13. Effect of epothilones on the tubulin polymerization. 74

Fig. 14. Effect of epothilones on the colocalization of β-tubulin and p50. 75

Fig. 15. Effects of epothilones, IKK inhibitor, and cell death regulatory protein inhibitor on the expressions of apoptosis regulatory proteins, NF-κB activation, and cell death. 79

Fig. 16. Effect of epothilones on the vascular smooth muscle cell proliferation induced by FBS and PDGF-BB. 88

Fig. 17. Effect of EPOs on the apoptosis induction of VSMCs. 91

Fig. 18. Effects of epothilones on the p53 expression and nuclear accumulation in VSMCs. 95

Fig. 19. Effects of p53 inhibitor and siRNA p53 on the epothilone-induced apoptosis and p53 expression. 98

Fig. 20. Effect of epothilones on the expression of Bax and caspase-3 activation in VSMCs. 101

Fig. 21. Effects of EPOs on the neointimal hyperplasia and VSMCs apoptosis of neointimal layer after balloon injury. 104

Fig. 22. Effect of epothilones on the activations of p53 and caspase-3 proteins in neointimal hyperplasia. 106

Fig. 23. Representative mechanisms of epithilone-induced apoptotic cell death in colon cancer cell and excessive VSMCs proliferation. 120

초록보기

Epothilone은 현재 항암제로 사용되고 있는 탁솔이나 탁소텔 등과 같이 Microtubule(미세소관)을 안정화시켜 세포분열을 억제함으로써 암 세포의 증식을 막아 줄 수 있는 물질이다.

혈관 평활근세포(vascular smooth muscle cell, VSMC)의 증식은 동맥경화증의 주요 원인으로 알려져 있다. 따라서 본 논문에서는 Epothilone의 과도한 세포증식 억제 가능성을 이용하여 Human colon cancer SW620 세포와 혈관평활근세포(VSMC) 증식에 대한 억제효과와 작용 기작을 규명했다.

Epothilone B와 D를 처리한 군의 경우 대장암 세포를 농도의존적으로 저해하였으며 epothilone들에 의해 cell cycle이 arrest(G₂/M)되어 apoptosis가 일어났다. epothilone B와 D는 IkB kinase (IKKα and IKKβ)를 통해 IkB degradation을 유발시켜 NF-κB를 활성화 시켰으며 결과적으로 nucleus로 p50과 p65의 translocation을 일으켰다. 또한 epothilone B와 D은 β-tubulin polymerization과 p50/β-tubulin complex의 형성도 증가시켰다. IKK 저해제인 Sodium salicylic acid을 첨가하거나 IKKα 변이주를 사용하였을 때에 β-tubulin polymerization은 증가되지 않았으나 NF-κB dependent apoptotic cell death regulatory genes인 Bax, p53, caspase-3는 증가시켰다. Caspase-3 inhibitor, 사용 시 epothilone B-induced cell death와 NF-kB 활성을 감소 시켰다.

이상의 결과를 통해 NF-κB/IKK 신호가 tubulin polymerization에 비의존적으로 epothilone에 의해 유도되는 대장암세포 SW620 사멸에 중요한 역할을 담당하는 것을 알 수 있었다.

흰쥐경동맥 손상모델에서 Epothilone B와 D의 신생내막형성 억제효과와 흰쥐경동맥 평활근세포(VSMC)의 증식을 촉진 시키는 성장인자의 변화도 조사 하였다. 혈소판유래 성장인자인 PDGF-BB처리 시 apoptosis가 유도되지 않았으나, EPOs를 첨가한 실험결과 epothilone B와 epothilone D는 유의적으로 VSMC의 세포사멸을 유도하였으며 전형적인 세포사멸 염색사의 형태적 변화와 함께 세포의 원형화와 플레이트로부터 탈착이 관찰 되었다. EPOs 처리군의 경우 cell cycle이 arrest(G0/G₁)되어 apoptosis가 일어나는 것을 알 수 있었다. 또한 EPOs는 세포핵내의 p53발현을 증가시켰으며 이들 p53의 전좌(translocation)가 세포사멸의 주요한 요인임을 확인 하였다. 신호전달 연구를 통해 epothilone B와 D가 p53의 발현과 축적을 유도하였으며 p53조절 caspase-3와 Bax가 활성화 되는 것을 알 수 있었다. 이러한 현상은 Paclitaxel을 양성대조군으로 사용한 rat carotid artery ballooninjury model의 동물실험을 통해 epothilone B, D, 그리고 Paclitaxel 투여로 신생내막형성이 유의적으로 억제되는 것을 확인하였다. 이상의 결과를 통해 epothilones의 신생내막형성억제 효과는 EPOs에 의해 활성화된 p53-dependent caspase-3 경로를 경유한 VSMC의 세포사멸에 기인함을 알 수 있었다.

참고문헌 (99건) : 자료제공( 네이버학술정보 )

참고문헌 목록에 대한 테이블로 번호, 참고문헌, 국회도서관 소장유무로 구성되어 있습니다.
번호 참고문헌 국회도서관 소장유무
1 Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. 네이버 미소장
2 Epothilones and related structures--a new class of microtubule inhibitors with potent in vivo antitumor activity. 네이버 미소장
3 Inhibition of the p53 Tumor Suppressor Gene Results in Growth of Human Aortic Vascular Smooth Muscle Cells 네이버 미소장
4 Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. 네이버 미소장
5 The NF-kappaB and I-kappaB Proteins: New Discoveries and Insights 네이버 미소장
6 Sensitization of Taxol-induced Apoptosis by Curcumin Involves Down-regulation of Nuclear Factor-kappaB and the Serine/Threonine Kinase Akt and Is Independent of Tubulin Polymerization 네이버 미소장
7 Sabarubicin- (MEN 10755) and Paclitaxel Show Different Kinetics in Nuclear Factor-KappaB (NF-kB) Activation: Effect of Parthenolide on their Cytotoxicity 네이버 미소장
8 Mechanisms of angioplasty and stent restenosis: implications for design of rational therapy 네이버 미소장
9 In-stent stenosis: pathology and implications for the development of drug eluting stents. 네이버 미소장
10 Nocodazole, a microtubule depolymerising agent, induces apoptosis of chronic lymphocytic leukaemia cells associated with changes in Bcl-2 phosphorylation and expression 네이버 미소장
11 Microtubule-targeted anticancer agents and apoptosis. 네이버 미소장
12 Cytostatic activity of paclitaxel in coronary artery smooth muscle cells is mediated through transient mitotic arrest followed by permanent post-mitotic arrest: comparison with cancer cells. 네이버 미소장
13 Epothilone and paclitaxel: unexpected differences in promoting the assembly and stabilization of yeast microtubules. 네이버 미소장
14 Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action 네이버 미소장
15 Involvement of nuclear factor kappaB in c-Myc induction by tubulin polymerization inhibitors. 네이버 미소장
16 15-Deoxy-Delta^1^2^,^1^4-prostaglandin J~2 inhibition of NF-kappaB-DNA binding through covalent modification of the p50 subunit 네이버 미소장
17 Over-expression of Bcl-2 against Pteris semipinnata L-induced apoptosis of human colon cancer cells via a NF-kappa B-related pathway. 네이버 미소장
18 Induction of heme oxygenase-1 is involved in anti-proliferative effects of paclitaxel on rat vascular smooth muscle cells 네이버 미소장
19 The Synthesis of Amino Acid Bridged Dicatechol Derivatives 네이버 미소장
20 Desoxyepothilone B: An Efficacious Microtubule-Targeted Antitumor Agent with a Promising in vivo Profile Relative to Epothilone B 네이버 미소장
21 In-Stent Restenosis in the Drug-Eluting Stent Era 네이버 미소장
22 (2003) Nanomolar concentrations of epothilone D inhibit the proliferation of glioma cells and severely affect their tubulin cytoskeleton. J Neurooncol 65:99- 106. 미소장
23 Docetaxel (Taxotere): Preclinical and General Clinical Information 네이버 미소장
24 Glucocorticoids Selectively Inhibit Paclitaxel-Induced Apoptosis: Mechanisms and Its Clinical Impact 네이버 미소장
25 Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-kappaB Activation 네이버 미소장
26 Enhanced Microtubule-Dependent Trafficking and p53 Nuclear Accumulation by Suppression of Microtubule Dynamics 네이버 미소장
27 p53 is associated with cellular microtubules and is transported to the nucleus by dynein 네이버 미소장
28 Epothilones: Mechanism of Action and Biologic Activity 네이버 미소장
29 The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo 네이버 미소장
30 Microtubules and signal transduction 네이버 미소장
31 The efficacy and safety of ixabepilone monotherapy in the treatment of breast and gynecologic malignancies 네이버 미소장
32 Epothilone D affects cell cycle and microtubular pattern in plant cells 네이버 미소장
33 The Stent-Eluting Drugs Sirolimus and Paclitaxel Suppress Healing of the Endothelium by Induction of Autophagy 네이버 미소장
34 The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. 네이버 미소장
35 Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. 네이버 미소장
36 Nuclear Factor-kappaB Induced by Doxorubicin Is Deficient in Phosphorylation and Acetylation and Represses Nuclear Factor-kappaB-Dependent Transcription in Cancer Cells 네이버 미소장
37 IkappaB kinase activation is involved in regulation of paclitaxel-induced apoptosis in human tumor cell lines. 네이버 미소장
38 The Possible Correlation Between Activation of NF-kappaB/IkappaB Pathway and the Susceptibility of Tumor Cells to Paclitaxel-Induced Apoptosis 네이버 미소장
39 Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells. 네이버 미소장
40 Nuclear Factor-kB/IkB Signaling Pathway May Contribute to the Mediation of Paclitaxel-induced Apoptosis in Solid Tumor Cells 네이버 미소장
41 Role of IkappaB kinase in tumorigenesis. 네이버 미소장
42 Co-Expression of p53 and MDM2 in Human Atherosclerosis: Implications for the Regulation of Cellularity of Atherosclerotic Lesions 네이버 미소장
43 Topographical Association Between the Cyclin-Dependent Kinases Inhibitor P21, p53 Accumulation, and Cellular Proliferation in Human Atherosclerotic Tissue 네이버 미소장
44 Molecular Mechanisms of In-Stent Restenosis and Approach to Therapy with Eluting Stents 네이버 미소장
45 Epothilone induced cytotoxicity is dependent on p53 status in prostate cells 네이버 미소장
46 Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization 네이버 미소장
47 Gold compound auranofin inhibits IkappaB kinase (IKK) by modifying Cys-179 of IKKbeta subunit 네이버 미소장
48 IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal 네이버 미소장
49 Microtubules and actin filaments: dynamic targets for cancer chemotherapy 네이버 미소장
50 Total syntheses of epothilones B and d. 네이버 미소장
51 Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. 네이버 미소장
52 Repeat motifs of tau bind to the insides of microtubules in the absence of taxol 네이버 미소장
53 Epothilone D, a microtubule-stabilizing compound, inhibits neointimal hyperplasia after rat carotid artery injury by cell cycle arrest via regulation of G1-checkpoint proteins 네이버 미소장
54 Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally different sesquiterpene lactones correlates with their effect on activation of NF-κB11Abbreviations: Con A, concanavalin A; HBSS, Hanks’ balanced salt solution; IL, interleukin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; NF-κB, nuclear factor kappaB; NO, nitric oxide; PEC, mouse peritoneal exsudate cell; TNF-α, tumor necrosis factor α; and Sl(s), sesquiterpene lactone(s). 네이버 미소장
55 Activities of the Microtubule-stabilizing Agents Epothilones A and B with Purified Tubulin and in Cells Resistant to Paclitaxel (Taxol[R]) 네이버 미소장
56 BMS-247550: A Novel Epothilone Analog with a Mode of Action Similar to Paclitaxel but Possessing Superior Antitumor Efficacy 네이버 미소장
57 Synthesis toward Epothilone A : Coupling Reaction between the Sulfone of C1-C10 and the Allylic Bromide of C11-C21 소장
58 Kaurane diterpene, kamebakaurin, inhibits NF-kappaB by directly targeting the DNA-binding activity of p50 and blocks the expression of antiapoptotic NF-kappaB target genes 네이버 미소장
59 Induction of apoptotic cell death by 2'-hydroxycinnamaldehyde is involved with ERK-dependent inactivation of NF-kappaB in TNF-alpha-treated SW620 colon cancer cells. 네이버 미소장
60 p53, the cellular gatekeeper for growth and division. 네이버 미소장
61 Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor kappaB by inhibiting the inhibitor of kappaB kinase. 네이버 미소장
62 Inhibition of transcription factor NF-κB signaling proteins IKKβ and p65 through specific cysteine residues by epoxyquinone A monomer: Correlation with its anti-cancer cell growth activity 네이버 미소장
63 Intracellular superoxide induces apoptosis in VSMCs: role of mitochondrial membrane potential, cytochrome C and caspases. 네이버 미소장
64 Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. 네이버 미소장
65 Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. 네이버 미소장
66 Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins 네이버 미소장
67 Natural products in cancer chemotherapy: past, present and future 네이버 미소장
68 Transfection of antisense p53 tumor suppressor gene oligodeoxynucleotides into rat carotid artery results in abnormal growth of vascular smooth muscle cells. 네이버 미소장
69 Endogenous p53 Protects Vascular Smooth Muscle Cells From Apoptosis and Reduces Atherosclerosis in ApoE Knockout Mice 네이버 미소장
70 Macrophage-Specific p53 Expression Plays a Crucial Role in Atherosclerosis Development and Plaque Remodeling 네이버 미소장
71 Effect of p53 Deficiency on External Vascular Cuff-Induced Neointima Formation 네이버 미소장
72 Cyclosporin-A Enhances Docetaxel-Induced Apoptosis through Inhibition of Nuclear Factor-kappaB Activation in Human Gastric Carcinoma Cells 네이버 미소장
73 The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography. 네이버 미소장
74 Molecular responses of vascular smooth muscle cells to paclitaxel-eluting bioresorbable stent materials. 네이버 미소장
75 Synthesis of epothilones A and B in solid and solution phase. 네이버 미소장
76 STRUCTURAL INSIGHTS INTO MICROTUBULE FUNCTION 네이버 미소장
77 Adenovirus-encoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis 네이버 미소장
78 Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease 네이버 미소장
79 Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis 네이버 미소장
80 Leptin Counteracts Sodium Butyrate-induced Apoptosis in Human Colon Cancer HT-29 Cells via NF-kappaB Signaling 네이버 미소장
81 Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury 네이버 미소장
82 p53 gene transfer to the injured rat carotid artery decreases neointimal formation. 네이버 미소장
83 The physiological function of drug-transporting P-glycoproteins 네이버 미소장
84 Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53: Implications for Brachytherapy and Drug Treatment for Restenosis 네이버 미소장
85 Melittin Inhibits Vascular Smooth Muscle Cell Proliferation through Induction of Apoptosis via Suppression of Nuclear Factor-kappaB and Akt Activation and Enhancement of Apoptotic Protein Expression 네이버 미소장
86 Apoptosis-regulated survival of primarily extravascular cells in proliferative active poststent neointima 네이버 미소장
87 Macrophage p53 Deficiency Leads to Enhanced Atherosclerosis in APOE^*3-Leiden Transgenic Mice 네이버 미소장
88 Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. 네이버 미소장
89 Regression of Atherosclerosis 네이버 미소장
90 The effect of antimicrotubule agents on signal transduction pathways of apoptosis 네이버 미소장
91 The biology and medicinal chemistry of epothilones. 네이버 미소장
92 The Epothilones and Related Analogues-A Review of Their Syntheses and Anti-Cancer Activities 네이버 미소장
93 Randomized trial of rapamycin- and paclitaxel-eluting stents with identical biodegradable polymeric coating and design 네이버 미소장
94 Drug-eluting stents. 네이버 미소장
95 Investigation of Antitumor Effects of Synthetic Epothilone Analogs in Human Myeloma Models in vitro and in vivo 네이버 미소장
96 Endothelin attenuates apoptosis in human smooth muscle cells. 네이버 미소장
97 Arsenic trioxide eluting stent reduces neointima formation in a rabbit iliac artery injury model 네이버 미소장
98 Transfer of Wild-Type p53 Gene Effectively Inhibits Vascular Smooth Muscle Cell Proliferation In Vitro and In Vivo 네이버 미소장
99 Calphostin-C Induction of Vascular Smooth Muscle Cell Apoptosis Proceeds through Phospholipase D and Microtubule Inhibition 네이버 미소장

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