臺灣博碩士論文加值系統

惡性黑色素瘤是一日漸增加且致命性高的惡性腫瘤，早期診斷及手術切除對於原位癌及初期患者大多可以治癒；但對於較晚期、侵襲性較高的腫瘤患者，除非接受全身性化學治療或免疫療法，其預後是相當不理想的。全身性化學治療或免疫療法的副作用都相當大，如噁心、嘔吐、落髮、骨髓抑制等。
丹蒽醌是中藥材—大黃的萃取物，大黃素、蘆薈大黃素、大黃酸皆為蒽醌類的活性化合物，亦都是大黃的主成分之一。研究者發現大黃素、蘆薈大黃素及大黃酸可經由阻礙細胞週期來抑制細胞生長，並主要經由粒線體路徑誘導多種癌細胞株細胞凋亡，也發現它們有明顯的抑制轉移作用。本研究在探討丹蒽醌對人類惡性黑色素瘤細胞株誘發細胞週期停滯及細胞凋亡之影響。實驗結果指出，丹蒽醌可經由細胞週期停滯在G0/G1 phase及誘導細胞凋亡，對人類惡性黑色素瘤細胞株產生細胞毒殺作用。DAPI染色及Comet assay觀察到DNA受損情形。流式細胞儀及即時聚合酶連鎖反應發現丹蒽醌經由降低粒線體膜電位後釋放cytochrome c、AIF及Endo G到細胞質中；也可增加Bax及抑制Bcl-xL/Bcl-2的表現並活化caspase-9及caspase-3後啟動caspase-dependent或caspase-independent的凋亡路徑。細胞內鈣離子濃度的增加可能導致粒線體膜電位下降及活性氧濃度上升。另外，丹蒽醌也可經由活化caspase-8及Bid/tBid促使cytochrome c釋放。因此，丹蒽醌可經由粒線體路徑、內質網路徑及死亡受體路徑誘發人類惡性黑色素瘤細胞株（A375.S2）的凋亡。

Malignant melanoma is an increasing common malignancy and with high mortality. Melanoma in situ and early stage melanoma could be cured if early diagnosis and surgical excision. Unless chemotherapy or immunotherapy, the prognosis is quite poor in patient of late staging and highly invasive malignancy. But the side effects of chemotherapy or immunotherapy are severe, such as nausea, vomiting, hair loss and bone marrow suppression.
Danthron is one of the extracts of Rhubarb that is a traditional Chinese herb. Danthron, Emodin, Aloe-emodin, and Rhein are all active compounds of Rhubarb. Researchers find that Emodin, Aloe-emodin, and Rhein can suppress cell growth via arresting cell cycle. They also can induce apoptosis of a lot of cancer cell lines via mitochondrial pathway and inhibit metastasis. This research is being probed into effects of Danthron on the induction of cell cycle arrest and apoptosis in human malignant melanoma cell line (A375.S2). The result suggests that Danthron can kill A375.S2 cells associated with G0/G1 phase arrest and induction apoptosis. DNA damage was found by DAPI stain and Comet assay. Flow cytometric assay and real time PCR showed that Danthron can decrease mitochondrial membrane potential and let releasing cytochrome c, AIF and Endo G to cytoplasm. Danthron increased expression of Bax and suppressed expression of Bcl-xL/Bcl-2 then active caspase-9 and caspase-3. Finally, it induced apoptosis of A375.S2 cells through caspase-dependent or caspase-independent pathway. Elevation of intracellular calcium concentration may decrease mitochondrial membrane potential and increase reactive oxygen species. Otherwise, Danthron could make cytochrome c to release via activating caspase-8 and Bid/tBid. In conclusion, Danthron can induce apoptosis through mitochondrial, endoplasmic reticulum and death receptor pathway in human malignant melanoma cell line (A375.S2).

目錄
致謝………………………………………………………………………i
中文摘要……………………………………………………………ii
英文摘要………………………………………………………………iii
目錄………………………………………………………………………v
圖目錄…………………………………………………………………vii
表目錄…………………………………………………………………ix
第一章 前言……………………………………………………………1
第二章 文獻探討
第一節 Danthron簡介………………………………………………3
第二節 人類惡性黑色素瘤簡介……………………………………5
第三節 細胞週期調控與其調控因子
一、細胞週期………………………………………………………13
二、細胞週期調控因子……………………………………………15
第四節 細胞死亡
一、細胞壞死………………………………………………………18
二、細胞凋亡
(一)細胞凋亡的定義…………………………………………18
(二)細胞凋亡特徵……………………………………………19
(三)細胞凋亡機轉……………………………………………20
第三章 研究設計
第一節 實驗用藥……………………………………………………30
第二節 實驗設計……………………………………………………31
第四章 材料與方法
第一節 實驗材料
一、細胞株…………………………………………………………33
二、藥品試劑………………………………………………………34
三、設備與器材……………………………………………………39
第二節 實驗方法
一、藥品配製………………………………………………………41
二、細胞培養………………………………………………………41
三、利用倒立式相位差顯微鏡檢測細胞型態……………………44
四、流式細胞儀分析
(一)細胞存活率測定………………………………………45
(二)細胞週期分析…………………………………………47
(三)活性氧化物產生之檢測………………………………49
(四)鈣離子濃度之檢測……………………………………50
(五)粒線體膜電位之檢測…………………………………52
(六)caspase-3、caspase-8、caspase-9活性分析檢測…………54
五、DNA損傷之檢測
(一)DAPI(4-6-diamidine-2-phenylindole)染色……………56
(二)彗星試驗………………………………………………57
六、西方點墨法
(一)細胞總蛋白的抽取……………………………………59
(二)蛋白質濃度測定………………………………………60
(三)SDS-PAGE變性電泳分析………………………………61
(四)西方點墨法……………………………………………64
七、即時聚合酶連鎖反應偵測細胞凋亡相關分子mRNA之表現（caspase-3、caspase-8、caspase-9、AIF、Endo G）………67
第三節 統計方法……………………………………………………68
第五章 實驗結果
第一節 丹蒽醌（Danthron）對人類惡性黑色素瘤細胞株（Human malignant melanoma cell line A375.S2）細胞數目、型態的影響……………………………………………………………70
第二節 Danthron對A375.S2 cells存活率之影響…………………72
第三節 Danthron對A375.S2 cells細胞週期之影響………………75
第四節 Danthron對A375.S2 cells的凋亡路徑之探討……………78
第五節 Danthron對A375.S2 cells的凋亡機制之探討……………86
第六節 利用西方點墨法探討Danthron對A375.S2 cells細胞週期停滯之相關蛋白質表現………………………………………90
第七節 利用西方點墨法探討Danthron對A375.S2 cells細胞凋亡之相關蛋白質表現……………………………………………94
第八節 以即時聚合酶連鎖反應（real time PCR）偵測caspase-3、 caspase-8、caspase-9、AIF、Endo G………………………104
第六章 討論…………………………………………………………106
第七章 結論…………………………………………………………118
結論總圖……………………………………………………………120
參考文獻……………………………………………………………121

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