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研究生:吳長霖
研究生(外文):Chang-Lin Wu
論文名稱:Phenethylisothiocyanate(PEITC)與Benzylisothiocyanate(BITC)經由氧自由基(ROS)與粒線體路徑誘導人類骨肉瘤細胞U-2OS細胞凋亡
論文名稱(外文):PEITC and BITC induce in human osteosarcoma U-2 OS cells apoptosis through ROS-and mitochondria-dependent pathways
指導教授:鍾景光鍾景光引用關係
指導教授(外文):Jing-Gung Chung
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:生物科技學系碩士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:108
中文關鍵詞:Benzyl isothocyanate (BITC)Phenethyl isothocyanate (PEITC)活性氧基群一氧化氮粒線體膜電位細胞凋亡
外文關鍵詞:Benzyl isothocyanate (BITC)Phenethyl isothocyanate (PEITC)reactive oxygen space (ROS)mitochondrial membrane potential (ΔΨm) and apoptosis
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由過去研究發現,Benzyl isothocyanate (BITC)與Phenethyl isothocyanate (PEITC)在動物模式下可以抑制化學致癌物引起癌化與腫瘤生成,但對於人類骨肉瘤的形成尚未有相關研究。本論文主要以人類骨肉瘤U-2 OS細胞株作為研究對象,探討PEITC與BITC引起U-2 OS細胞凋亡與抑制轉移之機制。首先U-2 OS細胞經PEITC與BITC不同濃度與時間處理後,檢測其細胞存活率、細胞週期與凋亡情況,活性氧基群之表現、粒線體膜電位變化、粒線體膜氧化現象,以及細胞內染色體凝集與DNA損傷及蛋白質在細胞內的分佈。結果顯示,PEITC與BITC能夠引起U-2 OS細胞細胞週期停滯於G2/M期及誘導細胞凋亡,其作用是有時間與劑量的依存性。PEITC與BITC誘導U-2 OS細胞內ROS與NO表現上升,導致細胞內粒線體與DNA受到氧化傷害,引起DNA損傷與膜電位下降,而導致粒線體內 Cytochrome c、AIF、Endo G蛋白質釋放到細胞質,並且活化Caspase-9引起下游Caspase-3表現量增加,使細胞經由粒線體路徑引起細胞凋亡。且PEITC與BITC能夠抑制細胞移動能力與細胞外MMP-2與MMP-9活性,進而抑制癌細胞轉移。
Previous animal model studies have shown that benzyl isothocyanate (BITC) and phenethyl isothocyanate (PEITC) inhibit carcinogenesis and tumorigenesis. However, the effects of BITC and PEITC on the formation of human osteosarcom are still not clear. In this study, we investigated whether BITC and PEITC can induce apoptosis and inhibit invasion of human osteosarcom U-2 OS cells. After BITC and PEITC were treatment on U-2 OS cells in various doses and time, by measuring cell viability, cell cycle, cell apoptosis, reactive oxygen species (ROS) production, mitochrondrial membrane potential (MMP) change, DNA damage, protein translocation, cell migration and invision ability, we foud that both PEITC and BITC could lead to cell death in a time- and dose- dependent manner. Both compounds also caused cell cycle arrest in G2/M phase, DNA damage, MMP decrease and mitochrondrial membrane oxidation which were stimulated by ROS and NO production. Furthermore, after treated with both compounds caused cytochrome c, AIF and Endo G released from mitochrondria and regulated apoptosis associated protein, such as caspase-9 and caspase-3, and then led to apoptosis in U-2 OS cells. In addition, PEITC and BITC could inhibit U-2 OS cells migration and invasion through suppressed the activity of matrix metallproteinase 2 (MMP-2) and MMP-9. Those results suggest that both PEITC and BITC induce human osteosacroma U-2 OS cells apoptosis through ROS- and mitochrondrial-dependment pathway.
總目錄
總目錄 …............................................................................................ I
表目錄 …............................................................................................ V
圖目錄 …............................................................................................ VI
致謝...................................................................................................... X
縮寫表 …............................................................................................ XII
中文摘要 ............................................................................................ XIII
英文摘要 ............................................................................................ XIV
第一章 前言........................................................................................ 1
第一節 研究背景........................................................................... 1
一、 惡性腫瘤治療與預防........................................................... 1
二、 異硫氰酸鹽 (Isothiocyanate) 與癌症............................... 6
三、 人類骨肉瘤 (Human osteosarcoma).................................. 9
四、 細胞凋亡 (Apoptosis)........................................................ 10
五、 細胞週期 (Cell cycle)........................................................ 14
六、 活性氧自由基群 (Reactive oxygen species, ROS)........... 17
七、 癌細胞轉移與侵襲............................................................. 19
第二節 研究目的........................................................................... 21
第二章 材料與方法 .......................................................................... 22
第一節 實驗材料…..…………..................................................... 22
一、細胞株來源..………………………………………………. 22
二、藥品試劑..…………………………………………………. 22
三、儀器設備與器材..…………………………………………. 24
第二節 實驗方法........................................................................... 26
一、 Phenethyl isothiocyanate (PEITC) 與Benzyl isothiocyanate (BITC) 配製..…………………………….
26
二、 人類骨肉瘤細胞株U-2 OS細胞培養…….……………. 26
三、 細胞冷凍保存與活化..…………………….…………….. 27
四、 細胞存活率 (Viability) 分析..………………………… 28
五、 細胞週期 (Cell cycle) 分析..…………………………… 29
六、 細胞內核質變化..………………………………………... 30
七、 細胞核質濃縮現象..…………………………………….. 31
八、 彗星試驗 (Comet assay).....…………………………....... 32
九、 細胞內活性氧化物質(Reactive oxygen species, ROS)測定...………………………………………………………..
33
十、 細胞內一氧化氮(Nitric oxide, NO)含量測定..………… 34
十一、 粒線體膜電位(Mitochondrial membrane potential,?n???卌).........…………………………………..
35
十二、 粒線體膜氧化程度測定...…………………………….. 36
十三、 免疫螢光染色...……………………………………….. 37
十四、 西方點墨法 (Western blotting).........…………………. 38
十五、 細胞凋亡測定..………………………………………... 42
十六、 細胞移動試驗…………………....……………………. 44
十七、 基質金屬蛋白酶(Matrix metalloproteinases, MMPs)活性測定...……………………………………………..
45
十八、 統計分析 (Statistics analysis).…………………….….. 46
第三章 研究結果………..………………………………..………… 47
第一節 Phenethyl isothiocyanate (PEITC) 與Benzyl isothiocyanate (BITC) 對U-2 OS 細胞生長之影響......
47
第二節 PEITC 與BITC 對U-2 OS 細胞株細胞週期之影響… 50
第三節 PEITC 與BITC 對U-2 OS 細胞株DNA 之影響....... 56
第四節 PEITC 與BITC 對U-2 OS 細胞產生活性氧物質能力之影響…………………………………………………...
60
第五節 PEITC 與BITC 對U-2 OS 細胞產生一氧化氮 (Nitric oxide, NO) 之影響……………………………...
66
第六節 PEITC 與BITC 對U-2 OS 細胞粒線體之影響…..… 71
第七節PEITC 與BITC 對U-2 OS 細胞誘導凋亡之影響……. 79
第八節 PEITC 與BITC 對U-2 OS 細胞移動(migration)之影響……………………………………………………....... 85
第九節 PEITC 與BITC 對U-2 OS 細胞MMP-2,-9 活性之影響…………………………………………………….......
87
第四章 討論………………………………………………………… 89
第五章 結論………………………………………………………… 94
第六章 參考文獻…………………………………………………… 96


表目錄
表 1-1-1. 基質金屬蛋白酶與其對應受質.......................................... 20
表 2-2-1 PI 染劑. ................................................................................ 29
表 2-2-2 SDS-PAGE下層膠 (Separating gel)之配製及組成............. 40
表 2-2-3 SDS-PAGE上層膠 (Stacking gel)之配製及組成.. .. .......... 40
表 2-2-4 電泳緩衝液 (Electrophoresis running buffer) ..................... 40
表 2-2-5 轉漬緩衝溶液 (Transfer buffer)........................................... 41


圖目錄

圖 1-1-1. 1986至2007年台灣地區十大死因死亡率………………. 5
圖1-1-2 飲食中植物抗癌化學成分…………………………………. 7
圖 1-1-3 ITCs 化學結構式…………………………………………... 16
圖 1-1-4 細胞凋亡內在路徑與外在路徑…………………………… 12
圖 1-1-5 細胞凋亡內質網壓力路徑………………………………… 13
圖 1-1-6 細胞週期調控機制………………………………………… 16
圖 1-1-7 細胞內抗氧化機制與氧化傷害機制……………………… 18
圖 1-2-1 研究目的…………………………………………………… 21
圖 2-2-1 MTT 原理圖解說明…………………...…………………... 28
圖 2-2-2 蛋白質轉漬順序…………………….……………………... 41
圖2-2-3 細胞凋亡分析………………………………………………. 42
圖 3-1-1 U-2 OS細胞經PEITC或BITC處理不同濃度與時間後細胞型態變化………..………………………………………
48
圖3-1-2 不同濃度與時間點PEITC (A)與BITC (B)對U-2 OS細胞存活率的影響………………………………………………
49
圖 3-2-1 流式細胞儀分析圖譜……………………………………… 51
圖 3-2-2 不同濃度PEITC對U-2 OS細胞24小時(A)與48小時(B)細胞週期之影響…………………………………………...
52
圖 3-2-3不同濃度BITC對U-2 OS細胞24小時(A)與48小時(B)細胞週期之影響………………………...…………………
53
圖 3-2-4 PEITC與BITC對U-2 OS細胞核內染色質之影響……… 54
圖 3-2-5 利用西方墨點法觀察PEITC與BITC對U-2 OS細胞週期調控蛋白之影響...………………………………………
55
圖 3-3-1 以Comet assay 觀察U-2 OS 細胞經PEITC 與BITC 誘導後DNA損傷程度……………….................................... 57
圖 3-3-2 Comet assay 拖尾程度量化圖…………..………………… 58
圖 3-3-3 以DAPI stain 觀察細胞染色質濃縮現象..…….………… 59
圖 3-4-1 U-2 OS細胞經PEITC (A)與BITC (B)誘導後ROS的表現. 61
圖 3-4-2 利用西方墨點法觀察PEITC與BITC對U-2 OS細胞抗氧化相關蛋白之影響.………………………………………
62
圖 3-4-3 經3 mM NAC預先處理再給予10 μΜ PEITC (A)與7.5 μΜ BITC (B)對U-2 OS細胞ROS產生之影響…………...
63
圖 3-4-4 經3 mM NAC預先處理再給予10 μΜ PEITC 與7.5 μΜ BITC 對U-2 OS細胞存活率之影響………………………
64
圖 3-4-5 U-2 OS 細胞先後處理3 mM NAC、10 μΜ PEITC (A)或7.5 μΜ BITC (B)對存活率之影響…………………..…......
65
圖 3-5-1 U-2 OS細胞經PEITC (A)與BITC (B)誘導後NO的表現... 67
圖 3-5-2 利用西方墨點法觀察PEITC與BITC對U-2 OS細胞一氧化氮合成相關蛋白之影響………………………….......
68
圖 3-5-3 利用西方墨點法觀察PEITC與BITC對U-2 OS細胞Nitro-tyrosine蛋白質表現量....………………..…………..
69
圖 3-5-4 經3 mM NAC預先處理再給予10 μΜ PEITC 與7.5 μΜ BITC 對U-2 OS細胞存活率之影響...…………………… 70
圖 3-6-1經3 mM NAC前處理再給予10 μΜ PEITC (A)與7.5 μΜ BITC (B)對U-2 OS細胞粒線體膜電位 (MMP,?n???卌) 之影響....................................................................................... 72
圖 3-6-2 PEITC (A)與BITC (B)對U-2 OS細胞粒線體膜氧化程度之影響………………...........................................................
73
圖 3-6-3 U-2 OS細胞經不同濃度cyclosporin A (CsA)預先處理後PEITC (A)與BITC (B)對細胞粒線體膜電位之影響..........
74
圖 3-6-4 U-2 OS細胞經3 mM NAC 預先處理後,PEITC (A)與BITC (B)對細胞粒線體膜電位之影響……………….…...
75
圖 3-6-5 經3 mM NAC預先處理再給予10 μΜ PEITC (A)與7.5 μΜ BITC (B)對U-2 OS細胞粒線體膜氧化之影響………
76
圖 3-6-6 細胞在經PEITC或BITC誘導後,利用免疫螢光染色法觀察U-2 OS細胞內粒線體釋放Cytochrome c之情形…
77
圖 3-6-7 經3 mM NAC預先處理後,PEITC 與BITC 誘導U-2 OS細胞Cytochrome c釋放之影響……………………………
78
圖 3-7-1 PEITC (A)與BITC (B)誘導U-2 OS細胞凋亡…………….. 81
圖 3-7-2 利用西方墨點法觀察PEITC與BITC對U-2 OS細胞細胞凋亡調控相關蛋白表現量之影響…………………...…
82
圖 3-7-3 U-2 OS細胞經PEITC或BITC誘導後AIF (A)與Endo G (B)自粒線體釋放至細胞核內………………….......……...
83
圖 3-7-4 利用西方墨點法觀察PEITC與BITC對U-2 OS細胞PARP與Caspase-3之影響…………………………………
84
圖 3-8-1 PEITC (A)與BITC (B)對U-2 OS細胞移動能力之影響…. 86
圖 3-9-1 PEITC與BITC對U-2 OS細胞MMP-2, -9活性之影響…. 88
圖 5-1 PEITC與BITC誘導人類骨源性肉瘤細胞株 U-2 OS細胞凋亡之路徑模式…………………...…………………………
95
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