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研究生:吳晶霓
研究生(外文):Jing-Ni Wu
論文名稱:以二氫二醇去氫酶為標的酵素篩選抗乳癌台灣原生植物
論文名稱(外文):Using DDH as a target enzyme for screening Taiwan native plants with anti- breast cancer activity
指導教授:周寬基周寬基引用關係
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生命科學院碩士在職專班
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:85
中文關鍵詞:二氫二醇去氫酶二氫二醇去氫酶二氫二醇去氫酶
外文關鍵詞:TCMDDHbreast cancer
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時至今日,乳癌的現行療法無論是手術摘除、放射治療、化學療程,長效性的賀爾蒙療法甚或近年盛行的標靶治療,效果仍然不彰,無法根本治療乳癌,更因為乳癌細胞天然之抗藥性,使治療更為棘手。因此,為了改進化療效果,本研究從88種青草藥萃取物,篩選具有乳癌特異性毒殺效果之台灣特有植物。DDH被證實在許多種癌細胞都有高度表現,而且和癌症的進程以及癌細胞的抗藥性提升相關。於是我們偵測五株乳癌細胞DDH表現情形。結果發現五株細胞DDH表現並不相同。選取DDH最高表現量的BT-20,以及表現量較低的MCF-7,分析其DDH的亞型,發現BT-20表現兩種亞行:AKR1C1及C3,MCF-7表現C1。利用WST-1細胞增生實驗我們篩選出10種萃取液對BT-20,而11種萃取物對MCF-7有抑制細胞增長效果,接著分析DDH與近年發現同樣與癌症抗藥性相關的ATAD3A受影響的情形,僅有編號37的BC同時對兩個蛋白在兩種細胞有類似的抑制作用。偵測PARP發現,雖然兩種細胞對BC敏感程度不同,卻都能觀察到PARP被切割的情形,而且隨著萃取液濃度提高PARP全長量逐漸減少。進一步觀察BC對Rad23A (在泛素調節機轉的中負責辨識泛素化蛋白的因子) 分布影響,發現使用BC後,細胞有自噬小泡累積的情況,而Rad23A則聚積在自噬小泡附近。由以上結果顯示,BC萃取液會降低DDH表現,與現行藥物並用或許能夠提高癌細胞對藥物的敏感程度,並且本身可能誘發癌細胞進行細胞凋亡與細胞自噬,極具抗乳癌新藥開發的潛力。

Nowadays, the existing treatments, including surgical removal, radiation therapy, chemotherapy, long-acting hormone therapy or even the emergence of the recent target therapy did not overcome the difficulties of the treatment. The major problem is the spontaneous resistance of cancer cells to the available drug. In order to improve the effectiveness of chemotherapy, our study screened 88 plant extracts in order to find out cancer-specific cytotoxicity of species unique to Taiwan. High expression of DDH was confirmed in many kinds of cancer, and was also correlated to carcinogenesis as well as increasing drug-resistant. Thus, we detected DDH levels in five breast cancer cell lines. The result showed differential expression of DDH. We further performed 2-D analysis of BT-20, which revealed the highest amount of DDH, and of MCF-7. It showed that BT-20 expressed AKR1C1 and C3, whereas MCF-7 displayed only C1. Using WST-1 assay, we found 10 extracts on BT-20 and 11 extracts on MCF-7 exhibited inhibitory effects on cell growth. We evaluated changes of protein levels of DDH and ATA3A, which is recently uncovered to relate to drug resistance associated with cancers. Only BC (#37) had inhibitory effects both on two proteins in two cells. Detection of PARP found that although two cells have different sensitivities to BC, it can be observed in the case of PARP has been cut, and with the amount of full-length PARP reducing in a dose-dependent manner. Observation of Rad23A (responsible for ubiquitinated proteins identification) distribution found that use of BC resulted in cells accumulating autophagic vacuoles, and Rad23A gathered in the vicinity of vacuoles. Taken together, BC reduced the DDH level hence the application of BC with existing drugs may be able to raise the sensitivity of cancer cells to drugs. Besides, BC may perform its effects through the induction of apoptosis and/or autophagy. Therefore our results showed BC to be with great potential in anti-breast cancer drug development.

目 錄
頁次
中文摘要 ---------------------------------------------------------------- Ⅰ
英文摘要 ---------------------------------------------------------------- Ⅱ
目 錄 ---------------------------------------------------------------- Ⅲ
表 目 次 ---------------------------------------------------------------- Ⅵ
圖 目 次 ---------------------------------------------------------------- Ⅶ
中英對照 ---------------------------------------------------------------- Ⅷ
第一章 緒論 --------------------------------------------------------- 1
一、 乳癌 (breast cancer)
(一) 全球與台灣乳癌發生之概況 ----------------------------- 1
(二) 乳癌分期 ---------------------------------------------------- 2
(三) 各種型態 ---------------------------------------------------- 2
(四) 發生機轉 ---------------------------------------------------- 3
(五) 診斷、治療及預防 ----------------------------------------- 4
二、 二氫二醇去氫酶 (dihydrodiol dehydrogenase, DDH)
(一) DDH簡介 --------------------------------------------------- 5
(二) AKR超級家族 (aldo-keto reductase superfamily) ----- 5
(三) DDH與癌症 ------------------------------------------------ 6
三、 傳統中草藥 (traditional Chinese medicine, TCM)
(一) 傳統中草藥與癌症治療 ----------------------------------- 6
(二) BC 簡介 ----------------------------------------------------- 7
第二章 文獻探討 ----------------------------------------------------- 9
一、 程序性細胞死亡 (programmed cell death)
(一) 簡介 --------------------------------------------------------- 9
(二) 半胱氨酸蛋白酶 (caspase) -------------------------------- 10
(三) 細胞凋亡機轉Ⅰ:內生性路徑 (intrinsic pathway) --- 11
(四) 細胞凋亡機轉Ⅱ:外生性路徑 (extrinsic pathway) --- 12
(五) 細胞死亡與癌症 -------------------------------------------- 13
二、 ATAD3A (ATPase family, AAA domain containing 3A) 14
三、 Drp1 (dynamin-related protein 1) -------------------------- 14
四、 PARP [Poly(ADP-ribose) Polymerase] ------------------- 15
五、 RAD23A (RAD23 homolog A) ---------------------------- 15
第三章 研究動機 ---------------------------------------------------- 17
第四章 材料方法 ---------------------------------------------------- 18
一、 藥品、緩衝溶液、抗體、顯微鏡
(一) 藥品 ---------------------------------------------------------- 18
(二) 緩衝溶液 ---------------------------------------------------- 18
(三) 抗體 ---------------------------------------------------------- 18
(四) 顯微鏡 ------------------------------------------------------- 18
二、 細胞培養
(一) 細胞株 (Cell line) ------------------------------------------ 18
(二) 解凍細胞 ---------------------------------------------------- 18
(三) 細胞繼代 ---------------------------------------------------- 18
(四) 細胞計數 ---------------------------------------------------- 19
(五) 中草藥細胞增生測試 (WST-1 proliferation assay) ---- 19
(六) 免疫細胞螢光染色 (Immunofluorescence staining) --- 19
三、 蛋白質操作
(一) 細胞株萃取蛋白質 (Protein Extraction) ---------------- 20
(二) 蛋白質定量 ------------------------------------------------- 20
(三) 蛋白質二維電泳 -------------------------------------------- 20
四、 聚丙烯醯胺凝膠電泳 (SDS-PAGE) 及西方墨點法
(Western Blot)
(一) 膠體配置 ---------------------------------------------------- 21
(二) 蛋白質電泳及轉印------------------------------------------ 21
(三) 免疫反應 ---------------------------------------------------- 21
第五章 結果 ---------------------------------------------------------- 23
一、 DDH 在乳癌細胞株中的表現
(一) 五株乳癌細胞株中 DDH 的表現情形 ------------------ 23
(二) 二微電泳分析DDH亞型----------------------------------- 23
二、 偵測青草藥萃取液對乳癌細胞株中DDH表現量的影響
(一) 以WST-1篩選對乳癌細胞有毒殺效果的青草藥萃取
液 ------------------------------------------------------------- 23
(二) 青草藥萃取液對乳癌細胞DDH、ATAD3A與Drp1表
現量的影響 -------------------------------------------------- 24
三、 BC誘發乳癌細胞死亡的觀察
(一) 偵測PARP的表現與cleaved-PARP量的變化----------- 24
(二) 觀察Rad23A的表現 ---------------------------------------- 24
第六章 討論 ----------------------------------------------------------- 26
圖 表 ------------------------------------------------------------------ 29
參考文獻 ------------------------------------------------------------------ 50
附 錄 ------------------------------------------------------------------ 83


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