臺灣博碩士論文加值系統

本研究中，新合成的喹啉衍生物BV001對攝護腺癌(prostate cancer，PCa)細胞具有細胞毒性作用。BV001被發現能誘導攝護腺癌細胞株(PC3和PC/DX25)intra-S細胞週期之停滯而具有抗增殖作用。歐洲杉醇(docetaxel)為去勢抗性攝護腺癌(castration-resistant prostate cancer，簡稱CRPC)患者的一線化療藥。然而，幾乎所有患者於三至五個月內仍死於歐洲杉醇抗性之去勢抗性攝護腺癌。因此，CRPC患者的有效化學治療劑的發展已成為重要之議題。BV001用於攝護腺癌細胞株PC3和對歐洲杉醇具抗藥性之PC/DX25之研究。針對PC3和PC/DX25，BV001的IC50分別為1.75 ± 0.32和1.6 ± 0.28 μM，表明BV001在兩種細胞株皆具有細胞毒殺作用。BV001同時增加PC3及PC/DX25細胞內ROS的產生，ROS的產生量皆為控制組的1.5倍，ROS的產生是造成DNA受損的因素之一。細胞週期分析顯示，BV001處理於PC3和PC/DX25中，導致DNA受損而促使intra-S細胞週期停滯且處理時間增加凋亡細胞也隨之增加，由p-H2AX的表現證實DNA受損及intra-S及G2/M細胞週期蛋白的調控證實intra-S細胞週期停滯，如cyclin A、CDK2、cdc25c、cyclin B1及CDK1。由annexin V-FITC/PI雙染法更確認BV001誘導攝護腺癌凋亡結果。同時，西方點墨法結果顯示，BV001抑制Bcl-2的表現，增加Bax和Bad的表現，誘發細胞色素c(cytochrome c，cyto c)由粒線體膜釋放至細胞質，活化caspase 3及降解PARP，最終導致攝護腺癌細胞的凋亡。結論，BV001通過細胞週期intra-S停滯誘導攝護腺癌細胞凋亡，主要經由細胞內ROS的產生促使DNA受損，調控細胞週期intra-S相關蛋白的抑制及粒線體相關路徑調控。

In this study, BV001 is a new synthetic quinoline derivative with the cytotoxic effects in prostate cancer(PCa) cells. BV001 has been found to have the anti-proliferation in PCa cell lines(PC3 and PC/DX25) by arresting cell cycle in intra-S phase. Nowadays, the docetaxel-base therapies are used as a first-line chemotherapy for castration-resistant prostate cancer(CRPC) patients. However, almost all patients died from docetaxel-resistant CRPC during three to five months. Hence, the development of effective chemotherapeutic agents for CRPC patients has become imperative and important. Cytotoxicity of BV001 was examined in PC3 and PC/DX25(a docetaxel-resistant subline) by MTT assay. IC50 of BV001 in PC3 and PC/DX25 were 1.75 ± 0.32 and 1.6 ± 0.28 μM, respectively, indicating that BV001 was with the cytotoxic effects in both cell lines. BV001 increased the production of ROS in PC3 and PC/DX25 cells, and the ROS generation was 1.5 times than control group. ROS generation was one of the factors that caused DNA damage. Cell cycle analysis showed that BV001-treated PC3 and PC/DX25 leaded to DNA damage inducing intra-S phase arrest and increasing the deaths of apoptotic cell in time increasing. The results showed that the expression of p-H2AX confirmed DNA damage, and the modulation of intra-S and G2/M cell cycle regulators, such as cyclin A, CDK2, cdc25c, cyclin B1 and CDK1, confirmed intra-S phase arrest. The results of annexin V-FITC/PI double staining assay also confirmed BV001-induced apoptotic prostate cancer. Simultaneously, the results showed BV001 medicated apoptosis of PCa cells through the down-regulation of Bcl-2, the up-regulation of Bax and Bad, the releasing of cytosol cyto c from mitochondria, the degradation of PARP and the activation of caspase 3 by Western blot. In conclusion, BV001 induces apoptosis of prostate cancer cells through cell cycle intra-S arrest because intracellular ROS production resulted in DNA damage which regulated cell cycle intra-S-related protein and mitochondrial-dependent signaling pathway.

壹、中文摘要1
貳、英文摘要(Abstract)2
參、前言4
肆、緒論5
一、喹喹啉(Quinoline)衍生物之介紹5
二、人類攝護腺及攝護腺癌之介紹7
(一)生理構造7
(二)流行病學7
(三)風險因子8
三、人類攝護腺癌治療之介紹10
(一)診斷方法10
(二)治療方法12
四、歐洲杉醇(Docetaxel)的抗藥性機制15
五、細胞凋亡機制21
六、細胞週期23
伍、研究動機26
陸、材料與方法27
一、實驗材料27
二、研究方法32
(一)細胞培養32
(二)細胞存活率試驗(MTT assay)33
(三)細胞週期分析34
(四)細胞凋亡分析35
(五)細胞內ROS含量試驗36
(六)西方點墨法36
柒、實驗結果40
一、BV001抑制攝護腺癌細胞株生長40
二、BV001誘導攝護腺癌細胞株細胞週期停滯於Intra-S期41
三、BV001誘導攝護腺癌細胞株凋亡與死亡42
四、BV001經由粒線體相關途徑誘導攝護腺癌細胞凋亡42
五、BV001調控攝護腺癌細胞MAPK途徑43
六、BV001誘導攝護腺癌細胞株DNA受損43
七、BV001調控攝護腺癌細胞株的細胞週期蛋白表現導致細胞週期停滯於intra-S期43
八、BV001誘導攝護腺癌細胞株ROS量增加44
捌、討論46
玖、結論52
壹拾、圖表53
壹拾壹、參考文獻72
壹拾貳、英文縮寫表79

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