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研究生：	謝長亨 Hsieh, Chang-Heng
論文名稱：	三唑化合物作為自噬促進劑用於疾病治療 Triazole derivatives as autophagy enhancers
指導教授：	方剛 Fang, Kang
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	161
中文關鍵詞：	細胞自噬、多麩醯胺酸、聚集物清除、三唑化合物、JNK訊息傳遞、神經退化疾病、人類非小細胞肺癌細胞、細胞凋亡
英文關鍵詞：	autophagic flux, polyglutamine, aggregates clearance, triazole, JNK pathway, neuronal disorders, human non-small-cell-lung-cancer cells, apoptosis
DOI URL：	https://doi.org/10.6345/NTNU202203506
論文種類：	學術論文
相關次數：	點閱：83 下載：6
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本論文目的是鑑定三唑衍生物潛在用於治療神經退化疾病及非小細肺癌細胞的藥物。多麩醯胺酸造成的神經退化性疾病是因為神經細胞中基因座上出現過度CAG三核甘酸的重複序列所導致的疾病。利用增加細胞自噬清除多麩醯胺酸堆積，是一種可能的方式用來治療多麩醯胺酸相關神經疾病。在第一部分的論文中，利用表現多麩醯胺酸的細胞模式篩選一系列的候選藥物。從一系列三唑衍生物中篩選出化合物的藥物OC-13,它可以透過增強自噬特性，清除外來質體衍生的蛋白質ΔC-TBP-Q79-EGFP或Httex1-Q97-GFP造成多麩醯胺酸堆積，卻不會影響細胞活性。由螢光顯微鏡下觀察，表現擴增多麩醯胺酸的細胞經OC-13處理增加自噬小體，會清除超過５０％的蛋白質堆積。由西方墨點法分析顯示，OC-13促進LC3-I轉換為LC3-II以增進自噬體形成，而自噬抑制劑能阻斷OC-13清除多麩醯胺酸的功能。
論文第二部分利用增強細胞自噬主導的第二型計畫性細胞死亡可以用作於癌症的治療。透過細胞活性分析, colony forming assay, Annexin V染色及西方墨點法分析，可以確認另一個三唑衍生物BTO會抑制人類非小細胞肺癌細胞的增生，並能隨著時間及濃度誘導自噬相關蛋白，並且促進凋亡，這都是透過自噬小體增加與溶酶體的形成。利用Annexin V染色及西方墨點法分析可以顯示促進自噬的BTO造成肺癌細胞的凋亡。此外由腫瘤組織的西方墨點分析和螢光顯微鏡中顯示，BTO可以抑制在小鼠模型中異種移植的A549腫瘤生長，並且誘導凋亡和自噬標記物的增生。

這兩種三唑衍生物化合物可以是抑制人類疾病的一種潛在治療藥劑。

Strategies that enhance autophagy clearance of polyQ accumulation have become an attractive approach to revive neuronal cell viabilities. In the part I of the dissertation, a selected autophagic enhancer candidate was identified as a cell model for polyQ aggregation clearance. The polyQ diseases were caused by expansion of CAG trinucleotide repeats in the coding region of gene. After screening a series of triazole derivatives, a newly identified synthetic compound, 5,5′-(4,4′-(1,3-phenylene-bis(oxy))-bis(methylene)-bis(1H-1,2,3-triazole-4,1-diyl))-bis(methylene)-bis(3-(naphthalene-1-yl)-oxazolidin-2-one (OC-13), was shown capable of enhancing clearance of the aggregated polyQ in neuroblastoma cells. Human neuroblastoma cells SK-N-SH with ectopic expression of ΔC-TBP-Q79-EGFP or Httex1-Q97-GFP mutant protein can be cleared of mutated aggregates without affecting cell viabilities. Treatment of OC-13 increased autophagosome formation and more than 50% the accumulated aggregates were eradicated as determined by fluorescence microscopy. Western blot showed that OC-13 converted LC3-I to LC3-II in the transfected cells and activated autophagy-mediated elimination of polyQ aggregation. The effects were repressed by autophagic inhibitors.

Autophagic enhancer is also a valid treatment strategy as cancer therapeutics. In the part II of the dissertation, another newly identified triazole derivative compound, 4-((5-benzyl-1H-1,2,4-triazol-3-yl)-methyl)-7-methoxy-2H-benzo[b][1,4]-oxazin-3(4H)-one (BTO), was found inhibiting the growth of human NSCLC cells. BTO induced autophagic characteristics and inhibited cell growth as shown in MTT evaluation, colony forming assay and Western blot. The compound induced autophagosome and autolysosome formation. More experiments with Annexin V staining and Western blot showed that the drug induced apoptotic cell death that was related to autophagy activation. Furthermore, BTO suppressed the growth of xenograft tumors by activating autophagy-mediated apoptosis as shown in Western blot and fluorescence microscopy of tumor tissue specimen staining.

The triazole derivatives OC-13 and BTO can be of potential therapeutic values to treat human diseases.

INDEX    5
CHAPTER I ABSTRACT    11
CHAPTER II 中文摘要    13
LIST OF ABBREVIATIONS    15
CHAPTER III AUTOPHAGY    17
CHAPTER IV    19
PART I THE APPLICATION AND MECHANISMS TO TREAT POLYGLUTAMINE DISEASES    19
I.    INTRODUCTION    19
1.    Protein aggregation diseases    19
2.    Triazole derivatives and neurodegeneration    19
3.    Autophagy and protein aggregation diseases    20
II.    MATERIAL AND METHOD    21
1.    Cell culture    21
2.    Plasmid and transfection    21
3.    Reagents    22
4.    FACScalibur analysis    24
5.    Immunoblotting    24
6.    Quantification of aggregation dots    25
7.    Confocal microscopy detection    25
8.    Statistical analysis    26
III.    RESULTS    27
1.    Establishment of inducible polyQ stable cell lines    27
2.    Autophagic enhancer screening    27
3.    More evidence of OC-13-activated autophagy.    28
4.    Amelioration of Q79-EGFP aggregates by OC-13    29
5.    The autophagic clearance is related to JNK signaling pathway activation    30
6.    Clearance of the Q79-EGFP aggregates by JNK-mediated autophagy    30
7.    Exclusion of nucleus polyQ aggregation    31
8.    Transient Httex1 polyQ transfection    31
9.    OC-13-induced autophagy in cells transfected with Httex1-Q97    32
10.    Phosphorylation of JNK and Akt are increased by OC-13 in Httex1-Q97 transfected cells    33
11.    OC-13 decreased Httex1-Q97 aggregations    33
12.    Elimination of Httex1-Q97 aggregation by OC-13-mediated autophagy    34
13.    Elimination of aggregates by JNK-mediated autophagy    34
IV.    DISCUSSION    36
CHAPTER V    40
PART II THE APPLICATION AND MECHANISMS TO TREAT HUMAN NON-SMALL CELL LUNG CANCER CELLS    40
I.    INTRODUCTION    40
1.    Lung cancer    40
2.    Triazole derivatives and cancer    40
3.    Autophagic cell death    41
4.    Cancer and autophagy    41
II.    MATERIAL AND METHOD    42
1.    Cell culture    42
2.    Plasmid and transfection    43
3.    Reagents    43
4.    FACScalibur analysis    47
5.    Immunoblotting    47
6.    Animals and treatments    48
7.    Histochemical staining    48
8.    Cell viability assay    49
9.    Colony forming assay    49
10.    Statistical analysis    49
III.    RESULTS    51
1.    BTO inhibited cell growth by apoptosis    51
2.    Enhancement of apoptosis and autophagy characters by BTO    51
3.    Autophagy-mediated apoptosis by BTO    52
4.    BTO increase ROS in A549 cells    52
5.    BTO repressed growth in nude mice bearing xenograft tumors    53
IV.    DISCUSSION    55
CHAPTER VI CONCLUSION    58
CHAPTER VII FIGURES    60
Figure 1. Establishment of polyQ disease cell models.    61
Figure 2. Screening of autophagy enhancing chemicals    63
Figure 3. Changes of cell viability and aggregation intensities by candidate compounds.    65
Figure 4. The variations of autophagy markers.    67
Figure 5. The candidate chemical OC-13 and cell viability determination    68
Figure 6. Activation of lysosome by OC-13.    71
Figure 7. Induction of autophagy markers by OC-13.    73
Figure 8. Inhibition of autophagy by Baf A1.    74
Figure 9. Autophagosome formation and aggregates clearance by OC-13.    76
Figure 10. Elimination of Q79 aggregation dots by OC-13.    77
Figure 11. Elimination of the insoluble EGFP by OC-13.    79
Figure 12. Activation of JNK pathway.    80
Figure 13. Elimination of Q79 aggregation by JNK pathway and autophagy.    82
Figure 14. Elimination of the insoluble EGFP as affected by inhibitors.    83
Figure 15. The increase of autophagosomes by JNK pathway.    85
Figure 16. Elimination of nucleus Q79 aggregation.    88
Figure 17. Clearance of nucleus Q79 aggregation by autophagy and JNK pathway.    90
Figure 18. Establishment of Httex1 Q25 and Q97 cell models.    91
Figure 19. Increasing of autolysosome by OC-13 in Httex1-Q25 and Q97-transfected cells.    93
Figure 20. Activation of lysosomes by OC-13 in Httex1-Q97 transfected cells.    95
Figure 21. Formation of autophagosome in Httex1-Q97 transfected cells.    96
Figure 22. Induction of autophagic markers in Httex1-Q97 transfected cells by OC-13.    98
Figure 23. Maintenance of cell viability in Httex1-Q97 transfected cells.    100
Figure 24. Activation of JNK, Akt and S6K in Httex1-Q97 transfected cells.    101
Figure 25. Elimination of aggregations in Httex1-Q97 transfected cells.    103
Figure 26. Elimination of the insoluble Httex1-Q97 aggregates by OC-13.    105
Figure 27. Clearance inhibition of aggregation.    107
Figure 28. Clearance inhibition of insoluble Httex1-Q97.    109
Figure 29. Elimination of Httex1 aggregation dots by JNK pathway and autophagy.    111
Figure 30. The increase of autophagosomes by JNK pathway in Httex1-Q97 transfected cells.    112
Figure 31. Summary of OC-13 induced polyQ clearance by autophagy.    113
FIGURE II    114
Figure 32. Inhibition of cell proliferation in human non-small cell lung cancer cells.    115
Figure 33. Activation of apoptosis by BTO.    118
Figure 34. Activation of autophagy and apoptosis by BTO.    119
Figure 35. Apoptosis and autophagy in adenocarcinoma.    121
Figure 36. Formation of autophagosome and autolysosome by BTO.    123
Figure 37. Repression of autophagic flux by 3-MA.    125
Figure 38. Inhibition of BTO-mediated apoptosis by 3-MA.    127
Figure 39. BTO-induced autophagic apoptosis in A549.    128
Figure 40. Increase of ROS intensity by BTO.    130
Figure 41. Inhibition of autophagy by NAC.    132
Figure 42. Inhibition of tumor growth in nude mice xenografts.    134
Figure 43. Increase of apoptosis in nude mice xenografts.    136
Figure 44. Decrease of proliferation and increase of autophagy in tumor.    138
Figure 45. Promotion of apoptosis marker in tumors.    140
Figure 46. Summary of BTO induced autophagy.    141
CHAPTER VIII REFERENCE    142
CHAPTER IX    APPENDIX    152
                                

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