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論文名稱(外文):Butein induced apoptosis through reactive oxygen species/ Mitogen-activated protein kinase pathway in breast cancer cells.
指導教授(外文):Li-Sung Hsu
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紫鉚花素是一種從Rhus verniciflua Stokes抽取的多酚類物質,目前研究發現紫鉚花素可以藉由產生過氧化壓力進而促使許多癌細胞死亡,但是紫鉚花素對於乳癌細胞的作用機制尚未完全厘清。在此研究,我們發現紫鉚花素可以抑制乳癌細胞生長為濃度以及時間依賴性。我們亦利用DNA濃縮以及細胞在sub-G1時期的百分比來偵測紫鉚花素促使細胞走向凋亡現象。紫鉚花素可以產生活性氧化物質並且抑制活化態ERK活性以及活化態AKT活性和增加活化態p-38。利用流式細胞儀的分析,可觀察到紫鉚花素同樣可使乳癌細胞產生大量ROS,之後再處理抗氧化劑N-acetyl-cysteine (NAC)不但能降低紫鉚花素所造成ROS的產生並且能減少紫鉚花素對乳癌細胞的毒殺效果。綜合我們的研究顯示紫鉚花素可以抑制乳癌細胞生長並透過活性氧化物質和經由MAPKs路徑和AKT 路徑,促使Bcl-2蛋白的下降,讓Caspase 3切割,接著引發PARP的斷裂,進而引發細胞凋亡。

Butein (3,4,2_,4_-tetrahydroxychalcone), a component of Rhus verniciflua Stokes,is known to induce several cancer cell death through oxidative stress, however, the direct involvement of oxidants in butein-induced breast cancer cell death remain unknown. In this study, we show that butein inhibited the proliferation of human breast cancer cell (MDA-MB-231) in a dose- and time-dependent manner. Treatment with butein also induced apoptosis as evidence by increasing DNA condensation and sub-G1 phase DNA content. Butein induced generation of reactive oxygen species (ROS) and accompanied with decreased the phosphorylation states of ERK and AKt and increased the phosphorylation states of p-38, decreased B-cell lymphoma-2 (Bcl2) expression, and was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage Pretreated with N-acetyl cysteine (NAC) which is a strong antioxidant agent abrogated butein-induced apoptotic effect, decreased ROS level, and recovered the phosaphorylation status of ERK , and reduced Bcl2, which consequently caused the cells to undergo apoptosis. Collectedly, our results revealed that butein induced apoptosis in breast cancer cells via generation of ROS and inhibited the activities of ERK and AKT, which can be reversed by pre-treated with antioxidant agent such as NAC.

中文摘要 I
英文摘要 II
誌謝 III
目錄 IV
縮寫表 VII
壹、緒論 1
一、癌症(Cancer) 2
二、乳癌(The introduction of Breast cancer) 3
三、 細胞凋亡 5
四、有絲分裂因子-活化蛋白質激酶路徑(mitogen-activated protein kinase pathways, MAPK pathways ) 8
五、PKB / Akt(protein kinase B ) 11
六、自由基與含氧自由基 11
七、細胞內產生ROS 的過程與預防機制 14
八、類黃酮(Flavonoids) 15
貳、研究動機 18
參、實驗材料與方法 19
一、化學藥劑 19
二、抗體 21
三、實驗材料 21
四、常用儀器 22
肆、實驗方法 23
(1)細胞株背景資料 23
(2)解凍細胞 24
(3)冷凍細胞 24
(4)細胞培養 25
(5)細胞數目計算 25
(6)細胞存活檢測(MTT cell viability assay) 26
(7)蛋白質濃度定量 27
(8)西方墨點法 28
(9)流式細胞分析法(Flow cytometry) 30
(10)DAPI(4'',6-DiAmidino-2-PhenylIndole) stain 32
(11)自由基的測量 (measurement of ROS Production) 33
伍、結果 35
一、 紫鉚花素 對 MDA-MB-231人類乳癌細胞存活率的影響 35
二、紫鉚花素透過誘導細胞凋亡造成MDA-MB-231人類乳癌細胞死亡 36
三、紫鉚花素 對 MDA-MB-231人類乳癌細胞株的細胞週期之影響 37
四、紫鉚花素 調控 AKT 與ERK以及p38訊息傳遞路徑 38
五、紫鉚花素影響與細胞凋亡的相關的蛋白 39
六、紫鉚花素促使細胞凋亡是透過活性氧化物質 40
陸、討論 43
柒、圖表與說明 47
捌、附錄 66
玖、文獻回顧 67

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1. Part I:藉由蛋白質體分析黃蓮素誘導乳癌細胞中之毒殺性機制 Part II:糖尿病 II-I:利用蛋白質體找出第一型糖尿病血漿生物標誌分子:發現 hemopexin為第一型糖尿病患者腎病血漿中新穎性生物標誌分子 II- II:藉由蛋白質體找出第二型糖尿病患者腎病血漿中生物標誌分子
2. Rersveratrol甲基衍生物3,5,3'',4'',5''–pentamethoxystilbene (MR-5)抑制人類乳癌細胞MCF-7生長及細胞週期G1停滯之分子研究
3. 褐藻糖膠在人類乳癌細胞中藉由提升泛素化TGFβ受器降解而降低TGFβ所引起的上皮-間質轉化過程
4. Tid1, CHIP 與 ErbB2 分子的相互作用以及它們對乳癌病人的影響
5. 輻射照射引發安全蛋白缺失之乳癌細胞老化其細胞間及分子機制之研究
6. 乳癌細胞存活機制之探討
7. 探討MCF-7乳癌細胞中常態堆積之XIAP:p19/p12-Casp7複合體作為I-Lys標靶
8. 肝細胞生長因子缺失體轉染乳癌細胞株的蛋白質體分析
9. 人體C1酯酶抑制蛋白對乳癌細胞增生與遷移的影響
10. 天然化合物致敏劑促進乳癌細胞MCF-7及MDA-MB-231之細胞凋亡
11. 癌症標靶材料作用於細胞與分子機制之探討:1.多光子趨動標靶化奈米鑽石誘發癌細胞死亡之機制;2.anti-CEACAM6與anti-HER-2單一抗原結合功能區抗體於乳癌標靶治療之研究。
12. 一種新穎化合物CR-108經由含氧自由基與粒線體損傷路徑誘發人類乳癌細胞的凋亡
13. 雌激素誘導4T1乳癌細胞於小鼠體內擴散之細胞機制
14. 天然植物化合物6-shogaol與pterostilbene抑制乳癌幹細胞特性及乳癌細胞侵入轉移之研究
15. 過量表現 gelsolin 對 MDA-MB-231人類乳癌細胞內肌動蛋白絲重組和細胞增生的影響