氧化鋅奈米粒子 (ZnO-NPs) 應用在防曬乳、食品添加、顏料、橡膠製造和電子材料上已日益增加。許多研究顯示ZnO-NPs可在多種人類癌細胞中會藉由產生氧化壓力抑制細胞生長，並且誘導細胞凋亡。然而，有關於ZnO-NPs在人類口腔癌細胞中的抗癌作用及分子機制尚未有清楚的研究。在本研究中，我們發現ZnO-NPs會抑制人類口腔鱗狀細胞癌Ca9-22細胞的生長，並呈濃度相關性誘發細胞凋亡。利用流式細胞儀分析細胞週期的變化，發現ZnO-NPs 可明顯地增加細胞sub-G1階段的累積。更重要的是我們發現ZnO-NPs不會損害正常細胞的存活率，如人類角質細胞 (HaCaT)，此結果顯示 ZnO-NPs可以選擇性在人類口腔鱗狀癌細胞產生細胞毒性。此外，ZnO-NPs 會誘導超氧化物的產生，並造成粒線體膜電位的喪失。抗氧化物殼胱甘肽 (GSH) 的前驅物 N-乙酰半胱胺酸(NAC) 會減少 ZnO-NPs 誘發的細胞死亡及超氧化物的生成。在西方點墨法的實驗則發現ZnO-NPs 會誘導caspase-3、caspase-7、caspase-9 及 PARP 的裂解，此結果顯示ZnO-NPs可經由caspase cascade誘發細胞凋亡。但是，ZnO-NPs 並沒有抑制pro-Bcl-2家族及抗氧化酶的蛋白表現。ZnO-NPs 也不影響 MAPKs激素，包括ERK1/2、JNK及p38的磷酸化。這些結果顯示，pro-Bcl-2家族及抗氧化酶的調控，以及MAPKs的訊息傳遞路徑，不會參與 ZnO-NPs 誘導細胞凋亡的過程。綜合以上結果，我們證明 ZnO-NPs 可能經由誘發超氧化物的生成以及粒線體的破壞，造成 caspase cascade的活化，最後促使人類口腔鱗狀癌細胞走向細胞凋亡。因此，我們認為ZnO-NPs 是一種具有潛力的抗癌物質，值得進行後續的藥物研發，應用於人類口腔鱗狀細胞癌的治療。

Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibits cell growth and induces apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer effect and molecular mechanism of ZnO-NPs in human oral cancer cells are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of human oral squamous cell carcinoma (OSCC) Ca9-22 cells. ZnO-NPs caused apoptotic cell death of Ca9-22 cells in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs in Ca9-22 cells. Importantly, ZnO-NPs did not impair the viability of normal cell types, like human keratinocytes (HaCaT cells), indicating ZnO-NPs may exerts the selective cytotoxicity in human OSCC cells.Furthermore, ZnO-NPs induced the generation of superoxide and loss of mitochondrial membrane potential. The antioxidant and glutathione precursor N-acetylcysteine significantly abolished ZnO-NPs-induced cell death and superoxide production. In addition, the immunoblotting assays showed that ZnO-NPs induced the activation of caspase-3, -7, and -9 and the cleavage of poly (ADP-ribose) polymerase, indicating the involvement of caspase-dependent cascade. However, ZnO-NPs did not inhibit the protein expression of pro-survival Bcl-2 family and antioxidant enzymes. ZnO-NPs also did not affect the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK, and p38. These results suggest that modulation of pro-survival Bcl-2 family and antioxidant enzymes as well as MAPKs signaling pathways are not involved in ZnO-NPs-induced apoptosis. Taken together, we demonstrate that ZnO-NPs may cause superoxide generation and mitochondrial disruption, leading to activation of caspase cascade, and subsequently apoptotic cell death in human OSCC cells.  Therefore, ZnO-NPs is a potential anti-cancer agent worthy of further development for treatment of human OSCC.

目錄
圖目錄	IV
表目錄	VI
第一章 前言	1
1-1 研究起源	1
1-2 研究目的	2
1-3 研究內容	3
第二章  文獻回顧	4
2-1 口腔癌	4
2-1-1 口腔癌之成因及特色	4
2-1-2 口腔癌之治療方式	5
2-2 光催化反應原理	8
2-2-1 半導體特性	8
2-2-2 光催化機制	9
2-3氧化鋅之特性與應用	14
2-3-1 氧化鋅晶形與結構	14
2-3-2 氧化鋅之應用	15
2-3-3 影響氧化鋅光催化反應之因素	16
2-3-4 氧化鋅奈米粒子相關的抗癌研究	18
2-4細胞凋亡(Apoptosis)	20
2-4-1細胞死亡的種類	20
2-4-2 ROS與細胞凋亡	21
2-4-3 粒線體與細胞凋亡	24
2-4-4 Caspase family與細胞凋亡	25
2-4-5 MAPK與細胞凋亡	27
2-4-6 細胞週期與細胞凋亡	28
第三章  實驗材料與方法	31
3-1 實驗儀器	31
3-2 實驗藥品及藥品配製	32
3-2-1 實驗藥品	32
3-2-2 Dulbecco’s Modified Eagle’s Medium (DMEM)培養基配製	33
3-2-3 Phosphate Buffered Saline (PBS) 配製	33
3-3 細胞株培養(Cell Culture)	34
3-4 MTT Assay 細胞存活率分析方法	37
3-5 Cell Death Detection ELISA	39
3-6 Reactive oxygen Species (ROS) 的測定	41
3-7 粒線體膜電位(△Ψm)的測定	42
3-8 西方墨點法-細胞蛋白質測定	43
3-8-1細胞內蛋白質分離	43
3-8-2蛋白質(protein)定量	43
3-8-3西方墨點法 (Western Blot)	44
3-9 利用Flow cytometry測定細胞週期變化	47
3-10 統計方法	47
第四章  實驗結果	48
4-1氧化鋅奈米粒子之光催化反應對人類口腔癌細胞生長之影響	48
4-2 改質TiO2-NPs對人類口腔癌細胞生長之影響	49
4-4 氧化鋅奈米粒子對其他人類癌細胞生長之影響	53
4-5 氧化鋅奈米粒子對人類正常角質細胞生長之影響	54
4-6 氧化鋅奈米粒子對人類口腔癌細胞凋亡之影響	55
4-7 氧化鋅奈米粒子刺激Reactive oxygen species (ROS)產生	56
4-8 氧化鋅奈米粒子對人類口腔癌細胞粒腺體膜電位之影響	58
4-9 氧化鋅奈米粒子對 Caspase family 之影響	59
4-10 氧化鋅奈米粒子對 Bcl-2 family 之影響	61
4-11 氧化鋅奈米粒子對 MAPK pathway 之影響	63
4-12 氧化鋅奈米粒子對 Antioxidant enzymes 之影響	64
4-13 氧化鋅奈米粒子對人類口腔癌細胞細胞週期之影響	65
第五章  結論與建議	67
5-1 結論	67
5-2 建議	70

圖目錄
圖 2 1光催化機制圖	10
圖 2-2 光觸媒圖解	11
圖 2-3常見之半導體之能隙分布圖	13
圖 2-4氧化鋅纖鋅礦結構	14
圖 2-5活性氧化物質(ROS)的生成及清除路徑	22
圖 2-6 NAC促進GSH生成路徑	23
圖 2-7 Bcl-2 family 之細胞凋亡路徑	25
圖 2-8 Caspase family 之細胞凋亡路徑	27
圖 2-9 細胞週期示意圖	30
圖 3-1 細胞計數盤	36
圖 3-2 MTT結構圖	37
圖 3-4 CDD 反應過程	39_Toc390720050
圖 4-1 低濃度氧化鋅奈米粒子之光催化反應對人類口腔癌細胞之影響	48
圖 4-2 改質二氧化鈦不同濃度及不同照射時間對Ca9-22細胞生長之影響	50
圖 4-3 氧化鋅奈米粒子對人類口腔癌細胞生長之影響	52
圖 4-3 氧化鋅對不同株細胞生長之影響	54
圖 4-5氧化鋅奈米粒子對人類正常角質細胞生長之影響	54
圖 4-6 氧化鋅誘導口腔癌細胞Ca9-22造成細胞凋亡	55
圖 4-7 氧化鋅奈米粒子刺激 ROS 及 Superoxide 的產生。	57
圖 4-8抗氧化劑 NAC 對氧化鋅奈米粒子抑制口腔癌細胞生長之影響	57
圖 4-9氧化鋅奈米粒子對人類口腔癌細胞粒腺體膜電位之影響	58
圖 4-10 氧化鋅奈米粒子對 Caspase family 之影響	60
圖 4-11 氧化鋅奈米粒子對 Bcl-2 family 之影響	62
圖 4-12 氧化鋅奈米粒子對MAPK pathway 之影響	63
圖 4-13 氧化鋅奈米粒子對 Antioxidant enzymes 之影響	64
圖 4-14 流式細胞儀分析	65
圖 5-1 ZnO-NPS 誘導Ca9-22凋亡可能之路徑圖	71

表目錄
表 2-1半導體之能隙寬度及光激發所需光波波長	12
表 2-2 ZnO基本物理性質	15
表 3-1 實驗儀器	31
表 3-2 實驗藥品	32
表3-3 PBS配方表	33
表3-4 SDS-PAGE 配方表	45
表4-1 改質二氧化鈦對乙烯之去除率	50
表4-2 以不同濃度之 ZnO-NPs 處理 Ca9-22 細胞，對細胞週期所造成的影響	66

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