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    題名: 氧化鋅奈米粒子誘導人類口腔癌細胞凋亡機轉之研究
    其他題名: ZnO nanoparticles-induced apoptotic mechanism in human oral squamous cancer cell
    作者: 林民生;Lin, Ming-Shen
    貢獻者: 淡江大學水資源及環境工程學系碩士班
    陳俊成;Chen, Luck
    關鍵詞: 氧化鋅;口腔癌細胞;細胞凋亡;活性氧化物質;粒線體膜電位;抗氧化酵素;細胞週期;Zinc Oxide;oral cancer cells;apoptosis;ROS;mitochondrial membrane potential;Antioxidant enzymes;Cell cycle
    日期: 2014
    上傳時間: 2015-05-04 10:03:00 (UTC+8)
    摘要: 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.
    顯示於類別:[水資源及環境工程學系暨研究所] 學位論文

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