在過去幾年中，分子生物學技術的發展強調了感染人類乳突病毒(human papillomavirus; HPV)以及使用檳榔、煙草和酒精的生活習慣等，皆可能透過導致染色體不穩定性或遺傳物質突變成為癌症的高風險因子，在口腔癌的癌變過程佔了很大的因素。病患的年齡及病兆的位置都會影響口腔癌的預後效果，目前的治療方式以手術切除搭配化學放療為主，但由於手術切除口腔組織影響吞嚥或咀嚼功能甚廣，且化學療法引起諸多嚴重的副作用，導致口腔癌的癌症五年存活率多年以來一直低於50%。因此找尋有效且低副作用的治療藥物與策略有其醫療價值。本論文探討了兩種分離自軟珊瑚之海洋天然物sinuleptolide和sinularin在口腔癌細胞株中具有調節細胞凋亡和細胞週期停滯的現象並且發現與氧化壓力有關。在藥物處理後出現誘導抑制細胞增殖、使細胞外觀具有凋亡形態、產生活性氧(reactive oxygen species; ROS)及粒線體超氧化物、細胞凋亡過程中磷脂醯絲胺酸(phosphatidylserine)外翻現象(annexin V染色法)和藉由觀測gamma H2A histone family member X (γH2AX)蛋白所偵測到的DNA損傷;此外，這些變化在正常細胞中皆有較低的毒性，且透過預處理活性氧抑制劑N-乙醯半胱氨酸(N-acetylcysteine; NAC)能防制毒性。綜合上述，本研究發現sinuleptolide和sinularin誘導了氧化壓力所造成的抗細胞增殖、G2/M細胞週期停滯，並且導致口腔癌細胞凋亡，展現海洋天然藥物用於氧化壓力治療法的抗癌潛力。

Over the past few years, the development of molecular biology techniques has highlighted the high cancerous risk factors such as human papillomavirus (human papillomavirus; HPV) infection, using betel nuts, tobacco and alcohol. These habits may cause chromosomal instability or genetic mutations are responsible for oral cancer carcinogenesis process. The patients' age and the location of tumor may affect the prognosis of oral cancer. The current treatment of oral cancer is surgical resection with adjuvant chemotherapy, but this surgical removal of tumor tissues affect swallowing and chewing function and chemotherapy usually generate side effects. The five-year survival rate of oral cancer has been below 50% for many years. Therefore, searching for effective anticancer drugs and strategies with lower side effects is valuable. This thesis investigated the anticancer effects of two marine natural products (sinuleptolide and sinularin) isolated from soft corals in terms of regulating apoptosis and cell cycle arrest in association with oxidative stress of oral cancer cell lines. Antiproliferation, apoptosis-like morphology, reactive oxygen species (ROS)/mitochondrial superoxide generation, annexin V-based apoptosis, and gamma H2A histone family member X (γH2AX)-based DNA damage were dose-responsively induced after treatments; moreover, all these changes were less harmful in normal cells and were rescued by ROS scavenger (N-acetylcysteine; NAC) pretreatment. Taken together, this thesis demonstrates that sinuleptolide and sinularin induce oxidative stress-mediated antiproliferation, G2/M arrest, and apoptosis against oral cancer cells and it presents potential oxidative stress-based anticancer therapy using these marine natural products.

論文審定書......i
誌謝......ii
摘要......iii
Abstract......iv
Contents......vi
List of Figures......xi
Chapter 1 Introduction......1
1.1 Oral cancer......1
1.2 Treatments of oral cancer......3
Chapter 2 Literature Review......5
2.1 New strategy for the treatment......5
2.2 Oxidation stress as anticancer strategy......5
2.3 Natural products for anticancer agents......6
Chapter 3 Experimental Section......9
3.1 Cell cultures and chemicals......9
3.2 Measurement of cell viability......10
3.3 Measurement of cell cycle distribution......11
3.4 Measurement of apoptosis by annexin V/propidium iodide (PI)......11
3.5 Measurement of apoptosis by poly (ADP-ribose) polymerase (PARP)......12
3.6 Measurement of intracellular reactive oxygen species (ROS) level......12
3.7 Measurement of mitochondrial membrane potential (MMP)......13
3.8 Measurement of DNA damage by comet assay......13
3.9 Measurement of DNA damage by gamma H2A histone family member X (γH2AX) assay......13
3.10 Mitochondrial superoxide production......14
3.11 Western blotting for G2/M arrest signaling......15
3.12 Apoptosis analysis by pancaspase......15
3.13 Apoptosis analysis by western blotting of caspases......16
3.14 Statistical analysis......16
Chapter 4 Sinuleptolide Inhibits Proliferation of Oral Cancer Cells Ca9-22 Involving Apoptosis, Oxidative Stress, and DNA Damage......18
4.1 Introduction......18
4.2 Results......19
4.2.1 Cell growth status in sinuleptolide treatment......19
4.2.2 Cell cycle status in sinuleptolide treatment......19
4.2.3 Apoptosis status in sinuleptolide treatment......20
4.2.4 ROS status in sinuleptolide treatment......20
4.2.5 MMP status in sinuleptolide treatment......21
4.2.6 DNA damage status in sinuleptolide treatment......21
4.3 Discussion......23
4.4 Illustrations......27
Chapter 5 Reactive Oxygen Species Mediate Soft Corals-Derived Sinuleptolide-Induced Antiproliferation and DNA Damage in Oral Cancer Cells......34
5.1 Introduction......34
5.2 Results......35
5.2.1 NAC effect on sinuleptolide-induced cell killing......35
5.2.2 NAC effect on sinuleptolide-induced morphology change......35
5.2.3 NAC effect on sinuleptolide-induced ROS generation......36
5.2.4 NAC effect on sinuleptolide-induced mitochondrial superoxide generation......36
5.2.5 NAC effect on sinuleptolide-induced γH2AX/PI-based DNA damage......37
5.3 Discussion......38
5.4 Illustrations......42
Chapter 6 Sinularin Induces Oxidative Stress-Mediated G2/M Arrest and Apoptosis in Oral Cancer Cells......48
6.1 Introduction......48
6.2 Results......49
6.2.1 Cell viability of sinularin-treated oral cancer cells and NAC pretreatment effect......49
6.2.2 ROS generation of sinularin-treated oral cancer cells Ca9-22 and NAC pretreatment effect......50
6.2.3 Cell morphology of sinularin-treated oral cancer cells Ca9-22 and NAC pretreatment effect......50
6.2.4 Cell cycle changes of sinularin-treated oral cancer cells Ca9-22 and NAC pretreatment effect......51
6.2.5 G2/M regulatory proteins of sinularin-treated oral cancer cells Ca9-22 and NAC pretreatment effect......51
6.2.6 Annexin V/PI-based apoptosis of sinularin-treated oral cancer cells Ca9-22 and NAC pretreatment effect......52
6.2.7 Caspases-based apoptosis of sinularin-treated oral cancer cells Ca9-22 and NAC pretreatment effect......53
6.3 Discussion......55
6.4 Illustrations......58
Chapter 7 Conclusion......67
References......71

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