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研究生:陳寬穗
研究生(外文):Kuan-Suei Chen
論文名稱:斑蝥素抑制人類攝護腺癌PC-3細胞生長、透過粒線體和caspase-3路徑誘發細胞凋零死亡
論文名稱(外文):Cantharidin inhibited cell growth and induced apoptosis in human prostate cancer PC-3 cells through mitochondrial- and caspase-3- dependent pathways
指導教授:葉兆雲
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:營養學系碩士班
學門:醫藥衛生學門
學類:營養學類
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:98
中文關鍵詞:斑蝥素人類攝護腺癌PC-3細胞週期粒線體caspase-3細胞凋亡
外文關鍵詞:Cantharidinapoptosishuman prostate cancerPC-3mitochondriacaspase-3cell cycle
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斑蝥素,在傳統中藥─斑蝥中能得此一成分,斑蝥學名為Mylabris phalerata,已有研究文獻顯示斑蝥素能夠抑制許多癌細胞的生長。一種男性惡性腫瘤─人類前列腺癌,具相當高的死亡率,而在其腫瘤發展、轉移過程中,常會造成不需要雄性激素癌細胞的生長,導致荷爾蒙抗性,最後死亡。然而,由於尚未有文獻研究指出斑蝥誘導人類前列腺癌細胞PC-3死亡,故此一實驗將斑蝥加入PC-3細胞,而後在不同時間作用下,以MTT實驗測試細胞存活率,並觀察特定的細胞型態,此外,以彗星試驗測試,斑蝥會造成PC-3細胞的DNA損傷。利用PI與DNA結合的特性,並以流式細胞儀偵測、分析細胞週期,發現斑蝥會誘導細胞週期停滯在G2/M期。而用DAPI與DNA結合的特性,觀察染色質濃縮現象,並用DNA洋菜膠體電泳法,觀察DNA片段,均發現斑蝥會誘導細胞凋亡。以鈣離子螢光結合劑,並用流式細胞儀偵測,顯示斑蝥會增加細胞內鈣離子濃度,而用親脂性陽離子化合物,與粒線體特異性結合染劑,並以流式細胞儀偵測,顯示斑蝥會降低粒線體膜電位。斑蝥亦會增加人類前列腺癌的caspase-3活性。這些結果指出,斑蝥透過粒線體路徑以及caspase-3路徑,來誘導細胞凋亡,且斑蝥未來可能作為癌症的治療藥劑,特別針對不需要雄性激素就能生長的人類前列腺癌細胞。
Cantharidin derived from traditional Chinese medicine, the blister beetle, Mylabris phalerata, and it had been shown to inhibit the growth of various cancer cells. Prostate cancer is one of most male malignancy which associated with high mortality. Advanced and metastasis cancer development with the growth of androgen-independent tumor cells results in hormone-refractory disease and leads to lethal death. However, there is no information to address cantharidin-induced cell death in human prostate cancer PC-3 cells. After treatment of PC-3 cells with cantharidin for various times, cell viability were examined by MTT assay and specific cellular morphology changes were observed. In addition, incubation of PC-3 cells with cantharidin led to increase DNA damage which were assessed by Comet assay. Cantharidin induced cell cycle arrest in G2/M phase and apoptosis, by staining with PI and determined by flow cytometry. The apoptotic evidences induced by cantharidin, including chromatin condensation and DNA fragmentation, are examined by DAPI staining and agarose DNA electrophoresis assay. Cantharidin increased cytosolic calcium (Ca2+) concentration and decreased the level of mitochondrial membrane potential (ΔΨm), which were stained with Ca2+ probe (Fluo-3/AM) and dihexyloxacarbocyanine iodide (DiOC6) then were analyzed by flow cytometry. Cantharidin also promoted caspase-3 activity in PC-3 cells. The results implied that cantharidin induced apoptosis through mitochondrial- and caspase-3- dependent pathways and it may be a potential cancer therapeutic agent in androgen-independent prostate cancer in future.
目錄
目錄 -------------------------------------------------------------------------------- i
圖目錄 ----------------------------------------------------------------------------- iv
表目錄 ----------------------------------------------------------------------------- vii
縮寫表 ----------------------------------------------------------------------------- viii
中文摘要 -------------------------------------------------------------------------- xiii
英文摘要 -------------------------------------------------------------------------- xiv
第一章 前言 --------------------------------------------------------------------- 1
第二章 文獻探討 --------------------------------------------------------------- 4
第一節 癌症生成(carcinogenesis)-------------------------------------- 4
第二節 人類前列腺癌(human prostate cancers)--------------------- 6
一、前列腺癌的病程 ------------------------------------------------------ 8
二、前列腺癌的危險因子 ------------------------------------------------ 12
三、前列腺癌的預防 ------------------------------------------------------ 13
四、前列腺癌的診斷 ------------------------------------------------------ 13
五、前列腺癌的治療 ------------------------------------------------------ 14
六、前列腺癌的預後 ------------------------------------------------------ 14
第三節 人類前列腺癌細胞株(human prostate cancer cell lines)-- 15
第四節 斑蝥素(cantharidin)--------------------------------------------- 17
第五節 細胞週期(cell cycle)-------------------------------------------- 19
一、細胞週期蛋白(cyclins)-------------------------------------------- 20
二、細胞週期蛋白依賴性激酶(cyclin-dependent kinases, CDK) 20
三、細胞週期蛋白依賴性激酶抑制因子(CKI)-------------------- 22
四、細胞週期檢查點(cell cycle checkpoint)------------------------ 23
第六節 細胞凋亡(apoptosis)-------------------------------------------- 25
一、細胞凋亡(apoptosis)與細胞壞死(necrosis)的比較 ------ 25
二、細胞凋亡的調控路徑 ------------------------------------------------ 28
第三章 材料與方法 ------------------------------------------------------------ 38
第一節 實驗目的與設計流程 --------------------------------------------- 38
第二節 實驗材料 ------------------------------------------------------------ 40
一、細胞株 ------------------------------------------------------------------ 40
二、藥品試劑 --------------------------------------------------------------- 40
三、儀器設備 --------------------------------------------------------------- 42
第三節 實驗方法 ------------------------------------------------------------ 43
一、斑蝥素(cantharidin)配製 ---------------------------------------- 43
二、細胞培養(cell culture)--------------------------------------------- 43
三、MTT試驗(MTT assay)-------------------------------------------- 46
四、細胞型態(cell morphology)觀察 ------------------------------- 49
五、彗星試驗(comet assay)-------------------------------------------- 49
六、DAPI染色(DAPI staining)--------------------------------------- 52
七、DNA斷裂分析(DNA fragmentation assay)-------------------- 54
八、細胞週期(cell cycle)分析 --------------------------------------- 57
九、鈣離子(Ca2+)濃度變化測定 ------------------------------------ 59
十、一氧化氮(nitric oxide, NO)生成測定 ------------------------- 61
十一、粒線體膜電位(MMP)變化測定 ----------------------------- 62
十二、caspase-3活性測定 ----------------------------------------------- 63
十三、統計分析(statistical analysis)--------------------------------- 64
第四章 結果 -------------------------------------------------------------------- 65
第一節 斑蝥素對PC-3細胞存活率的影響 ---------------------------- 65
第二節 斑蝥素對PC-3細胞型態的影響 ------------------------------- 67
第三節 斑蝥素對PC-3的DNA損傷影響 ----------------------------- 69
第四節 斑蝥素對PC-3染色質凝聚現象的影響------------------------ 71
第五節 斑蝥素對PC-3的DNA斷裂分析 ----------------------------- 73
第六節 斑蝥素對PC-3細胞週期的影響 ------------------------------- 74
第七節 斑蝥素對PC-3細胞內Ca2+濃度的影響 ---------------------- 78
第八節 斑蝥素對PC-3細胞內NO濃度的影響 ---------------------- 80
第九節 斑蝥素對PC-3粒線體膜電位的影響 ------------------------- 82
第十節 斑蝥素對PC-3 caspase-3活性的影響 ------------------------- 84
第五章 討論 --------------------------------------------------------------------- 86
第六章 結論 --------------------------------------------------------------------- 89
參考文獻 --------------------------------------------------------------------------- 90
圖目錄
圖2-1、化學致癌過程。--------------------------------------------------------- 5
圖2-2、前列腺各區疾病流行率。--------------------------------------------- 7
圖2-3、Gleason前列腺癌分級系統圖。------------------------------------- 12
圖2-4、各國家年齡層的前列腺癌發生率。--------------------------------- 13
圖2-5、基因變異與人類前列腺癌化過程。--------------------------------- 16
圖2-6、人類前列腺癌細胞PC-3的細胞型態。---------------------------- 16
圖2-7、斑蝥素的化學結構。--------------------------------------------------- 17
圖2-8、細胞週期。--------------------------------------------------------------- 19
圖2-9、細胞週期中cyclins蛋白表現變化。-------------------------------- 20
圖2-10、細胞週期中cyclin/CDK complex的調控。---------------------- 22
圖2-11、G2/M期檢查點(G2/M checkpoint)。---------------------------- 24
圖2-12、細胞凋亡PARP裂解。----------------------------------------------- 26
圖2-13、細胞凋亡DNA分段裂解。----------------------------------------- 27
圖2-14、在電子顯微鏡下,細胞凋亡與細胞壞死的不同型態。------ 27
圖2-15、細胞凋亡內在路徑及外在路徑。---------------------------------- 29
圖2-16、促凋亡蛋白及抗凋亡蛋白的結構。------------------------------- 30
圖2-17、細胞凋亡過程三階段。---------------------------------------------- 31
圖2-18、細胞凋亡形成apoptosome。---------------------------------------- 33
圖2-19、細胞凋亡外在路徑。------------------------------------------------- 35
圖2-20、內質網壓力正常的蛋白狀態。------------------------------------- 36
圖2-21、內質網壓力誘發細胞凋亡之路徑。------------------------------- 37
圖3-1、實驗流程圖。------------------------------------------------------------ 39
圖3-2、細胞計數。--------------------------------------------------------------- 45
圖3-3、MTT和MTT formazan的化學結構。------------------------------ 47
圖3-4、DAPI的化學結構。---------------------------------------------------- 53
圖3-5、EtBr的化學結構。----------------------------------------------------- 54
圖3-6、PI的化學結構。-------------------------------------------------------- 57
圖3-7、Fluo-3, AM的化學結構。--------------------------------------------- 60
圖3-8、DAF-FM diacetate偵測NO的反應途徑。------------------------ 61
圖3-9、DioC6(3)的化學結構。------------------------------------------------ 62
圖4-1、斑蝥素作用24、48、72小時的PC-3細胞存活率。----------- 65
圖4-2、斑蝥素10 μM作用不同時間的PC-3細胞存活率。------------ 66
圖4-3、斑蝥素作用24小時的PC-3細胞型態。--------------------------- 67
圖4-4、斑蝥素作用48小時的PC-3細胞型態。--------------------------- 68
圖4-5、斑蝥素10 μM作用不同時間的PC-3細胞型態。---------------- 68
圖4-6、斑蝥素作用24小時的PC-3彗星試驗結果。--------------------- 69
圖4-7、斑蝥素作用48小時的PC-3彗星試驗結果。--------------------- 70
圖4-8、斑蝥素作用24、48小時的PC-3彗星尾部長度。--------------- 70
圖4-9、斑蝥素作用24小時的PC-3染色質凝聚現象。------------------ 71
圖4-10、斑蝥素作用48小時的PC-3染色質凝聚現象。---------------- 72
圖4-11、斑蝥素作用24小時對PC-3的DNA斷裂分析。-------------- 73
圖4-12、斑蝥素作用24小時的PC-3細胞週期分布。------------------- 75
圖4-13、斑蝥素作用24小時的PC-3細胞週期分布量化。------------- 75
圖4-14、斑蝥素作用48小時的PC-3細胞週期分布。------------------- 76
圖4-15、斑蝥素作用48小時的PC-3細胞週期分布量化。------------- 76
圖4-16、斑蝥素10 μM作用不同時間的PC-3細胞週期分布。-------- 77
圖4-17、斑蝥素10 μM作用不同時間的PC-3細胞週期分布量化。-- 77
圖4-18、斑蝥素10 μM作用不同時間的Ca2+濃度變化。---------------- 78
圖4-19、斑蝥素10 μM作用不同時間的Ca2+濃度變化分析。---------- 79
圖4-20、斑蝥素10 μM作用不同時間的NO濃度變化。---------------- 80
圖4-21、斑蝥素10 μM作用不同時間的NO濃度變化分析。---------- 81
圖4-22、斑蝥素10 μM作用不同時間的粒線體膜電位變化。---------- 82
圖4-23、斑蝥素10 μM作用不同時間的粒線體膜電位變化分析。--- 83
圖4-24、斑蝥素10 μM作用不同時間的caspase-3活性變化。-------- 84
圖4-25、斑蝥素10 μM作用不同時間的caspase-3活性變化分析。-- 85
圖4-26、此實驗中,斑蝥素對PC-3影響。--------------------------------- 89
表目錄
表2-1、2002年前列腺癌TNM分級。----------------------------------------- 9
表2-2、前列腺癌臨床惡化四期。--------------------------------------------- 10
表2-3、細胞凋亡(apoptosis)與細胞壞死(necrosis)的比較。----- 28
表3-1、磷酸鹽緩衝液(PBS)配製。--------------------------------------- 44
表3-2、不同電泳條件所能偵測的DNA受損。---------------------------- 50
表3-3、彗星試驗法之lysis buffer配製。------------------------------------ 51
表3-4、Agarose gel配製。------------------------------------------------------ 55
表3-5、細胞週期分析之PI染劑配製。-------------------------------------- 58
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