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研究生：	劉俊彥 Liu, Chun-Yen
論文名稱：	透過活化p53引起人類非小細胞肺癌與肝癌細胞凋亡的吲哚喹嚀基藥物與其作用機制的探討 Study of a novel indolylquinoline compound that induces apoptosis in human non-small cell lung cancer and hepatocellular carcinoma cells through p53 activation
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：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	121
中文關鍵詞：	肺癌、p53 、EMMQ 、細胞凋亡、肝癌
DOI URL：	https://doi.org/10.6345/NTNU202203664
論文種類：	學術論文
相關次數：	點閱：142 下載：6
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肺癌是全世界癌症中死亡率第一的癌症。非小型細胞肺癌（NSCLC）佔肺癌病患的比例約75％至80％。化療所造成的副作用與抗藥性在肺癌治療中是有待處理的棘手問題。因此發展出新的抗癌藥物對肺癌的病患是有必要的。此篇論文旨在篩選可抑制肺癌細胞生長新穎的合成化合物。透過MTT的分析方式鑑定EMMQ對非小型肺癌細胞的IC50的濃度。數據顯示低濃度的EMMQ即可減少A549和H460此兩種非小型肺癌細胞的生長速率。研究也證明，EMMQ可誘導具有正常p53基因的非小細胞肺癌的細胞凋亡，而且該藥物對p53-null的非小細胞肺癌則無明顯的效果。研究顯示EMMQ會誘導細胞DNA損傷，活化p53蛋白，干擾粒線體的膜電位而釋放細胞色素c，造成Bcl-2的下降，活化caspase-3，讓PARP裂解而造成的內生性細胞凋亡。活體的實驗證明，EMMQ可以抑制裸鼠異種移植腫瘤的生長。最後，此研究證實EMMQ可在低濃度時活化非小細胞肺癌細胞的p53而造成細胞凋亡。此外，本研究還發現EMMQ可抑制具有正常 p53基因之非小細胞肺癌細胞的細胞轉移。因此本論文的數據顯示EMMQ可能成為一種新穎且有潛力的人類肺癌治療藥物。

肝癌是世界排名第五大常見的癌症。臨床顯示治療這些肝癌腫瘤中的重要的限制是治療過程中化療藥物長久投藥後的失效且肝癌對這些藥物產生抗藥性的問題。因此，開發肝癌治療中所產生化療失效與抗藥性的抗癌藥物是迫切需要的。之前我們已經確認EMMQ於肺癌細胞與活體的模式中是有效治療的效果。在此研究中證明EMMQ可抑制肝癌細胞的細胞生長進而誘導細胞凋亡。 EMMQ誘導的細胞凋亡為wild type p53的肝細胞癌（HCC）細胞，但是對mutant p53和p53-null細胞不敏感。數據顯示此化合物以內源性的途徑方式誘導細胞死亡。研究證明了EMMQ通過兩個主要途徑誘導細胞凋亡。此化合物使HepG2細胞的DNA損傷進而活化p53和γ-H2AX，降低cyclin D1和CDK 2的表現，導致細胞週期於G1期停滯。其次，此化合物使腫瘤抑制基因p53活化，干擾粒線體膜電位，使得ROS產生，Akt與 Bcl-2表現降低，Bax和細胞色素c的釋放，讓caspase-3和PARP裂解。細胞實驗的結果證明，在肝癌的治療上，EMMQ是一個有潛力的抗癌藥物。

Lung cancer is the leading cause of cancer mortality worldwide. NSCLC accounts for about 75% to 80% of lung cancer cases. Chemotherapy adverse side effects and resistance to current anticancer agents have been the pressing problems in the success of lung cancer therapy. Anticancer drugs are in urgent need especially for lung cancer. A program to develop a new anti-lung cancer agent by screening novel synthetic compounds was initiated.
EMMQ was selected by MTT cell viability assay. The cell growth rate of A549 and H460 NSCLC cells was reduced by a low concentration of EMMQ treatment. Our study revealed that EMMQ induced apoptosis in NSCLC cells with wild-type p53, while the drug is less potent to against p53-null cells. The study elucidated that EMMQ-induced apoptosis is was mediated through the intrinsic pathway involving DNA damage, activation of p53, interference of mitochondrial ΔΨm that led to release of cytochrome c and down regulation Bcl-2, activation of caspase family proteins, and finally cleavage of PARP polymerase cleavage.
In vivo study showed that EMMQ reduced tumorigenesis and significantly suppressed growth rate of xenograft tumors in nude mice. In addition, metastasis studies demonstrated that EMMQ may inhibit wild-type p53 cells migration at low concentration. In conclusion, EMMQ was demonstrated as an effective p53 regulator in NSCLC cells. Our findings indicate that EMMQ may serve as a promising new and potential therapeutic agent for human lung cancer.

Human liver cancer is the fifth most frequently diagnosed cancer worldwide. The important limitation in the clinical battle against this tumor is its marked intrinsic and acquired refractivity to the available chemotherapies. Anticancer agents effective against chemo-resistant cells are greatly needed for liver cancer treatment. Previously, our study have identified EMMQ as an effective drug in the treatment of lung cancer cells in vitro and in animal models. In this work, results show EMMQ treatment may inhibit cell growth and induce apoptosis in HCC. EMMQ induced apoptosis in HCC cells with wild-typed p53, and is less potent in cells with mutant p53 and in p53-null. The study also demonstrated that EMMQ induces apoptosis through two major pathways. First, the compound induced cell death through the intrinsic pathway by first damaging DNA increasing expression of p53 and γ-H2AX and decreasing cyclin D1 and CDK 2, finally leading to G1 arrest in HepG2 cells as studied cell cycle. Second, the tumor suppressor gene p53 was activated following a reduction of ΔΨm, ROS generation and down-regulating Akt, Bcl-2, Bax, cytochrome c, caspase-3 and cleavage of PARP, the critical events leading to cell death in HepG2 cells treated with EMMQ. The in vitro findings indicate that EMMQ is a promising candidate for the treatment of liver cancer.

Index
Page
Part Ⅰ
I.    ABSTRACT    5
II.    中文摘要    7
III.    INTRODUCTION    8
1.    Lung cancer    8
2.    Classification of lung cancer    8
3.    Small cell lung cancer    8
4.    Non-small cell lung cancer    8
5.    Squamous cell (epidermoid) carcinoma    8
6.    Adenocarcinoma    9
7.    Large cell (undifferentiated) carcinoma    9
8.    Other subtypes    9
9.    Apoptosis and p53    9
10.    Clinical treatment    11
11.    Novel synthesis of indolylquinoline derivative    12
12.    Aims of the study    13

IV.    MATERIALS AND METHODS    14
1.    Chemicals and cell culture.    14
2.    Cell viability assay.    14
3.    Colony forming assay.    15
4.    Comet assay.    15
5.    Determination of apoptosis.    16
Double staining with Annexin V-FITC and PI.    16
Cell-cycle distribution.    16
6.    Determination of ΔΨm.    17
7.    Release of cytochrome c release.    17
8.    Western blot analysis.    18
9.    Transfection with p53 shRNA.    18
10.    Xenograft tumor evaluation.    19
11.    Cell migration assay.    20
12.    Gelatin zymography    20
13.    Statistical analysis.    21

V.    RESULTS.    22
1.    EMMQ inhibits cell proliferation in both A549 and H460 cell………………………………………………………………….22
2.    EMMQ-induced DNA damage in wild-type p53 cell lines were examined by comet assay.    22
3.    The EMMQ increased sub-G1 population cells, G2/M arrest and apoptosis in both A549 and H460 cells.    23
4.    EMMQ-induced apoptosis through intrinsic pathway.    24
5.    The suppressed growth of xenograft tumors in EMMQ-treated A549 cells.    25
6.    The extent of EMMQ-induced apoptosis is dependent on p53 status.    26
7.    Down-regulated p53 abolished the onset of EMMQ-induced cell death in NSCLC cells    27
8.    The effect of EMMQ inhibited metastasis is dependent on Akt and β-catenin status.    28

VI.    DISCUSSION    30

VII.    CONCLUSION    35

VIII.    FIGURE AND LEGENDS    36
Figure 1  The structure of a new synthetic compound EMMQ and its inhibitory effect on cell growth of wild type p53 NSCLC cell lines.    36
Figure 2  EMMQ treatment inhibits growth of wild type p53 NSCLC cell lines    38
Figure 3  EMMQ treatment induces DNA damage in A549 and H460 cells.    40
Figure 4  EMMQ treatment induces change in cell cycle distribution in A549 and H460 cells.    42
Figure 5  Apoptosis induced by EMMQ in NSCLC cell lines.    45
Figure 6  EMMQ treatment induces apoptotic cell death in intrinsic pathway related proteins in A549 and H460 cells    47
Figure 7  EMMQ treatment causes apoptosis through reduced ΔΨm and enhanced cytochrome c release in A549 and H460 cells...    48
Figure 8  EMMQ inhibits growth of xenograft tumors by A549 cells in nude mice.    50
Figure 9  EMMQ treatment causes apoptosis through reduced ΔΨm on H1299 cells with stable expression of ectopic p53 cells.    53
Figure 10  EMMQ treatment induces change in cell cycle distribution on H1299 cells with stable expression of ectopic p53…    55
Figure 11  EMMQ treatment causes apoptosis through enhanced cytochrome c release on H1299 cells with stable expression of ectopic p53.    57
Figure 12  EMMQ treatment on p53 silencing in A549 and H460 cells proliferation.    59
Figure 13  EMMQ treatment reduces apoptotic cell death in intrinsic pathway related proteins on p53 silencing in A549 and H460 cells.    61
Figure 14  EMMQ inhibits cell migration of A549, H1299 and H460 cells.    62
Figure 15  Proposed mechanism for EMMQ-induced apoptotic cell death in NSCLS cells.    65













Part  II

I.    ABSTRACT    66
II.    中文摘要    67
III.    INTRODUCTION    68
1.    Liver cancer    68
2.    Aims of the study    68

IV.    MATERIALS AND METHODS    70
1.    Cell culture and reagent.    70
2.    Cell growth assay.    70
3.    Colony forming assay.    70
4.    Comet assay.    71
5.    Determination of apoptosis.    71
Double staining with Annexin V-FITC and PI.    71
Cell-cycle distribution.    71
6.    Measurement of intracellular ROS.    72
7.    ΔΨm assay.    73
8.    Analysis of cytochrome c release.    73
9.    Western blot analysis.    74
10.    Transfection with p53 shRNA.    74
11.    Isolation of mitochondria and cytosol fractions.    75
12.    Statistical analysis.    75

V.    RESULTS.    76
1.    EMMQ inhibited cell proliferation in human liver cancer cells….    76
2.    The EMMQ increased sub-G1 population cells, G1 arrest and apoptosis in HepG2 cells.    76
3.    EMMQ induces HepG2 cell apoptosis by way of DNA damage ..    78
4.    EMMQ-induced HepG2 cell apoptosis through intrinsic pathway of ΔΨm drop and cytochrome c release    79
5.    EMMQ induces HepG2 cell apoptosis through ROS production.    80
6.    EMMQ-induced apoptosis through intrinsic pathway.    81
7.    Down-regulated p53 abolished the onset of EMMQ-induced cell death in hepatocellular carcinoma cells    81

VI.    DISCUSSION    83

VII.    CONCLUSION    87

VIII.    FIGURE AND LEGENDS    88
Figure 16  Effect of EMMQ on cell growth in HCC cell lines and human hepatic cells.    88
Figure 17  EMMQ treatment induces change in cell cycle distribution, G1 phase cell cycle arrest and apoptosis ratio on HepG2 cells    91
Figure 18  EMMQ treatment induces DNA damage in HepG2 cell lines .    96
Figure 19  EMMQ induces ROS causes apoptosis through reduced ΔΨm and enhanced cytochrome c release in HepG2 cells….    99
Figure 20  EMMQ treatment induces apoptotic cell death in intrinsic pathway related proteins in HepG2 cells.    102
Figure 21  Effects of EMMQ treatment by p53 silencing in HepG2 cells    104
Figure 22  EMMQ treatment reduced DNA damage by p53 silencing in HepG2 cells    107
Figure 23  Proposed a model for EMMQ mediated apoptosis in HepG2 cells.    109

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