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研究生：	金承勳 Seung-Hun Kim
論文名稱：	消除人類癌腫瘤幹細胞的藥物 Human cancer stem cell tumor alleviation by therapeutic agents
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：	149
中文關鍵詞：	鴉膽子、三環氧化物、表皮生長因子受體、肺癌、中草藥、外源性途徑、肝癌、幹細胞
英文關鍵詞：	Brucea javanica, Teroxirone, epidermal growth factor receptor, human lung cancer, herbal medicine, extrinsic pathway, human liver cancer, stem cells
DOI URL：	https://doi.org/10.6345/NTNU202203304
論文種類：	學術論文
相關次數：	點閱：153 下載：15
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第一部分: 利用鴉膽子水溶液萃取物清除突變上皮細胞生長因子接受體人類肺癌細胞
中文摘要
從古以來，傳統草藥已經被大部分的中國人作為常用藥物，也是東方國家廣泛接受的藥物。非小細胞肺癌是最常見的肺癌類型，早期很難被診斷出。突變的表皮生長因子受體已經成為新型抗癌治療的分子標靶。本論文所使用鴉膽子水溶液萃取物有效地減弱了在非小細胞肺癌具有突變EGFR L858R/T790M的生長。癌幹細胞具有抗藥性，轉移和癌症復發，並且可以影響腫瘤治療的發展。重要的是，抗藥性使腫瘤更惡化。本論文也探討了鴉膽子水溶液萃取物對非小細胞肺癌的癌幹細胞的療效與反應機制。鴉膽子水溶液提取物是具可以成為非小細胞肺癌放射性治療有潛力的藥物。

第二部分: 發展teroxirone成為有效治療肝癌細胞的藥物
中文摘要
Teroxirone (1,3,5-tris((oxiran-2-yl)methyl)-1,3,5-triazinane-2,4,6-trione)是三環氧化物抗腫瘤劑，此研究目的是確定teroxirone如何調控與凋亡相關的細胞死亡。利用MTT檢測三種肝細胞癌細胞系：Huh7（突變體p53），HepG2（野生型p53）和Hep3B（p53-缺失型） assay(細胞存活檢測) 細胞存活率，利用流式細胞儀及西方點墨法觀察凋亡所導致的細胞死亡。本研究發現在Huh7 細胞所引起凋亡的細胞死亡是透過外在途徑。Teroxirone 可以誘導從Huh7腫瘤球體所純化出來的腫瘤幹細胞的凋亡並抑制Huh7腫瘤球體幹細胞特性。

Part-I. The alleviated tumorigenicity of human lung cancer cells carrying mutated epidermal growth factor receptor by aqueous extract of Brucea javanica
Abstract
The traditional herbal medicine has been used as convenient medicine by the majority of the Chinese population the since recorded history and is still a widely accepted medicine in oriental countries. NSCLC (non-small cell lung cancer) is the most prevalent type of lung cancers which is hard to be diagnosed early. The mutated EGFR (epidermal growth factor receptor) has become a target in the development of novel anti-cancer therapeutic approaches. In this study, the aqueous BJ (Brucea javanica) extract has found effectively attenuated the growth of human NSCLC with mutant EGFR L858R/T790M. CSCs (cancer stem cells) are involved in drug resistance, metastasis and relapse of cancers and can influence the tumor therapy development. Importantly, drug resistance makes tumors more malignant. The work investigated the underlying mechanisms of aqueous BJ extract against CSCs of NSCLC. The study showed potential implication of aqueous BJ extract as new target therapy to human lung cancer.

Part-II. The development of teroxirone as an effective therapeutic agent against human hepatocellular carcinoma cells
Abstract
Teroxirone is an experimental triepoxide antitumor agent. The purpose of this study is to determine how teroxirone regulates growth of liver cancer cell. Three hepatocellular carcinoma cell lines, Huh7 (mutant p53), HepG2 (wild-type p53) and Hep3B (p53-null) cells, were used for experiments. The study included MTT assay for assessing cell viability, flow cytometry for evaluating apoptotic cell death and Western blot analysis for determining signal pathway activation. The findings suggested that teroxirone induced apoptotic cell death in p53-mutated Huh7 by stimulating extrinsic pathway that was reverted by caspase-3 inhibitor. Teroxirone also induced apoptosis and suppresses the stemness properties of the enriched Huh7 spheroids. The study implied that the small molecular weight molecule teroxirone is a potentially valuable agent to treat human hepatocellular carcinoma.

ACKNOWLEDGEMENTS    2
LIST OF ABBREVIATIONS    3
Abstract    10
中文摘要    11
1. Introduction    12
1.1 The benefits of CHM    12
1.2 BJ as a conventional medicine    13
1.3 The prevalent lung cancer    14
1.4 EGFR in lung cancer    14
1.5 The CSCs hypothesis and drug resistance    16
1.6 Cancer stem cell markers in common cancers    17
2. Materials and methods    19
2.1 Cell culture conditions    19
2.2 The spheroid culture    19
2.3 Chemicals and reagents    20
2.4 Liquid chromatography/mass spectrometry analysis and instrumental conditions    20
2.5 Protein extraction and western blot analyses    21
2.6 Soft-agar colony formation assay    22
2.7 Immunofluorescence Staining    22
2.8 BrdU incorporation of spheroids    22
2.9 Tumor xenograft study    23
2.10 TUNEL assay    24
2.11 PCNA antibody staining for marker of proliferating cells in vivo    25
2.12 Statistical analysis    25
3. Results    26
3.1 LC/MS analysis of composition in aqueous BJ extract    26
3.2 The aqueous BJ extract induces apoptosis and reduced EGFR in H1975 cells    26
3.3 Effects of BJ on apoptotic features in H1975 cells    27
3.4 EGFR shRNA suppresses BJ sensitivities by inhibiting apoptosis    28
3.5 Oral administration of aqueous BJ extract inhibits xenograft tumor growth    28
3.6 Histological and fluorescence examination of the suppressed tumors    28
3.7 The aqueous BJ extract affects forming ability and proliferation in H1975 CSCs    29
3.8 The fluorescence cancer stem cell markers examination of the affected H1975 spheroids by aqueous BJ extract    30
3.9 The aqueous BJ extract induces apoptotic characteristics in H1975 spheroids    31
3.10 The aqueous BJ extract affects xenograft tumor growth in animal models nude mice    31
3.11 Fluorescence examination of the affected H1975 spheroid tumor by aqueous BJ extract    32
3.12 EGFR and cancer stem cell markers fluorescence examination of the affected H1975 spheroid tumor by aqueous BJ extract    33
3.13 The relapse of distinct stem cell signatures and drug resistance marker in spheroid tumors    33
3.14 The attenuated EMT and c-Met in tumors of mice fed with BJ    34
3.15 Histological examination of the collected organs    34
4. Discussion    35
Part-II. The development of teroxirone as an effective therapeutic agent against human hepatocellular carcinoma cells    40
Abstract    40
中文摘要    41
1. Introduction    42
1.1 Overview of liver cancer    42
1.2 An anticancer compounds teroxirone    43
2. Materials and methods    44
2.1 Cell culture conditions and treatments    44
2.2 The spheroid culture of HCC cells    44
2.3 MTT assay    45
2.4 Flow cytometry    45
2.5 Determination of apoptosis by double staining with Annexin V-FITC and PI    46
2.6 Protein extraction and western blot analyses    46
2.7 The effect of caspase-3 by z-DEVD-FMK    47
2.8 Spheroid formation assay    47
2.9 Soft agar colony formation assay    47
2.10 Immunofluorescence staining assay for spheres    48
2.11 Statistical analysis    48
3. Results    49
3.1 Dose-response growth curves of teroxirone in human hepatocellular carcinoma cells    49
3.2 Teroxirone increases apoptotic population of Huh7 cells by dose-dependent appearance of sub-G1 cells    49
3.3 Effects of teroxirone on apoptotic features in Huh7 cells    50
3.4 Inhibition of caspase-3 activity reduces apoptosis in HCC cells after treatment teroxirone    50
3.5 Teroxirone suppresses the growth of Huh7 spheroids    51
3.6 Teroxirone reduces stemness markers of Huh7 spheroids    51
3.7 Teroxirone induces apoptotic characteristics in Huh7 spheroids    52
4. Discussion    53
5. Conclusion    54
Figures    55
Figure 1. Chromatographic fingerprint analysis of the aqueous BJ extract    55
Figure 2. The aqueous BJ extract induces apoptosis and reduces EGFR in H1975 cells    59
Figure 3. Effects of teroxirone on apoptotic features in H1975 cells    61
Figure 4. EGFR shRNA suppresses BJ sensitivities by inhibiting apoptosis    63
Figure 5. Oral administration of aqueous BJ extract inhibited xenograft tumor growth    65
Figure 6. Histological and fluorescence examinations of the suppressed tumors    68
Figure 7. BJ reduces tumor growth by apoptosis    71
Figure 8. BJ suppresses H1975 spheroids growth    73
Figure 9. BJ reduces expression of stemness markers of H1975 spheres    76
Figure 10. BJ induces apoptotic characteristics of H1975 spheroids    79
Figure 11. Oral administration of BJ suppresses growth of tumor spheroid xenograft    82
Figure 12. BJ reduces spheroid tumor growth by apoptosis    85
Figure 13. Fluorescence examinations of the suppressed spheroid tumors    88
Figure 14. Fluorescence examination of the collected adherent cells and spheroid tumors    92
Figure 15. Fluorescence examination of the collected tumors    94
Figure 16. Histological examinations by H&E staining of the collected specimens    97
Figure 17. Dose-response growth of Huh7, HepG2 and Hep3B cells treated teroxirone    99
Figure 18. Teroxirone increases apoptotic population of Huh7 cells    102
Figure 19. Effects of teroxirone on apoptotic features in Huh7 cells    105
Figure 20. Teroxirone’s effects are reverted by z-DEVD-FMK in Huh7 cells    107
Figure 21. Caspase-3 inhibitor z-DEVD-FMK inhibits teroxirone-induced apoptosis in Huh7 cells    110
Figure 22. Model of FADD-mediated apoptosis induced by teroxirone in Huh7    111
Figure 23. Teroxirone suppresses the growth of HCC spheroids    114
Figure 24. Teroxirone reduces stemness and EMT markers of Huh7 spheres    117
Figure 25. Teroxirone induces apoptotic characteristics in Huh7 spheroids    120
References    122
Published paper 1    128
Published paper 2    139
                                

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