臺灣博碩士論文加值系統

以荷爾蒙療法治療荷爾蒙敏感型前列腺癌患者後期，將會演變為荷爾蒙抗性前列腺癌，之後以docetaxel合併其他藥物治療荷爾蒙抗性前列腺癌是第一線療法。臨床上此療法初期可獲得改善病況，但多年後仍有機會復發為docetaxel-resistant前列腺癌，因此對docetaxel抗藥性的研究是相當重要且迫切的。實驗室前人發現在具有docetaxel-resistant的前列腺癌細胞株中，EGFR的表達高於非抗藥性的細胞株，並與docetaxel抗性的產生有密切關係。因此本研究希望能篩選出新的化合物來抑制EGFR，以治療對docetaxel產生抗性的前列腺癌。首先以MTT測試Quinoline之衍生物對於PC3和PC/DX25的IC50，發現到代號為BV001、BV005及BV006這三個化合物有較低的IC50，而BV001對於PC3細胞株比具docetaxel抗性的PC/DX25細胞株，IC50高2.3倍。而利用MTT測試BV001、BV005及BV006對A431的毒殺性，發現其對BV001的敏感性也較高。接著利用Western blot及Real-Time PCR觀察處理化合物後PC3和PC/DX25兩株細胞株EGFR的表現，BV001明顯抑制了EGFR的表現。接著進一步探討其下游分子，發現在兩株細胞株中BV001抑制了STAT3的表現和AKT的表現，而p-ERK表現在PC3中受到誘導。接著觀察細胞凋亡相關分子的表現，發現兩株細胞株中抗凋亡分子的表現減少，而促進細胞凋亡的分子增加。而觀察ABCB1的表現，同時發現在兩株細胞株中ABCB1表現也減少。接著利用流式細胞儀觀察活性氧化物質(Reactive oxygen species, ROS) 產生情形，發現BV001會誘發ROS的產生。之後將ERK的活性抑制後，PC3對於BV001的敏感度增加。綜合以上結果，BV001會影響EGFR途徑而使細胞走向凋亡。

　Although hormone-sensitive prostate cancer could be treated by hormone therapy, it will eventually progress to castration-resistant prostate cancer (CRPC).The chemotherapeutic agent, docetaxel has been used as a prostate chemotherapy drug for years. Significant outcome has been observed in CRPC patients, but most of them will ultimately develop docetaxel resistance. Hence, to understand the mechanism behind development of drug resistance has become imperative and important. Previous research found that the docetaxel-resistant cell line PC/DX 25 expresses a higher EGFR level than PC3. This study aimed to screen new compounds that inhibit EGFR downstream as a treatment for docetaxel-resistant prostate cancer. First, the IC50 of quinoline-derived compounds were tested using MTT assay. BV001, BV005 and BV006 were found to have lower IC50. The cytotoxicity of BV001 was 2.3 folds higher in PC3 cells than in PC/DX 25 cells. Moreover, EGFR overexpression cell line, A431, had higher sensitivity to BV001 than other compounds. Real-time PCR and western blot analyses found that mRNA and protein levels of EGFR were reduced in both PC3 and PC/DX 25 cells after BV001 treatment. Examining downstream molecules revealed that BV001 inhibited the expression of STAT3 as well as the expression and activity of AKT in two cell lines. However, in PC3 cells, BV001 induced ERK activity. Furthermore, by western blot, after BV001 treatment, the expression of apoptosis-related molecules was up-regulated and the expression of anti-apoptotic molecules was down-regulated in both PC3 and PC/DX 25 cell lines. In addition, ABCB1 was reduced by BV001 treatment in these two cell lines. Flow cytometry found that reactive oxygen species (ROS) were produced in cells after BV001 treatment. After the activity of ERK was inhibited, PC3 increased its sensitivity to BV001. According to the above results, BV001 led cells to apoptosis via affecting the EGFR pathway.

中文摘要 1
Abstract 3
緒論 4
一、前列腺癌 5
二、前列腺癌化療藥物簡介 11
三、歐洲杉醇(Docetaxel)抗藥性機制 14
四、Quinoline 19
五、表皮生長因子受體Epidermal growth factor receptor (EGFR) 20
研究目的 23
材料與方法 24
I. 實驗材料 25
II. 研究方法 34
研究結果 44
一、篩選對於PC/DX25細胞株有較強毒殺性之化合物 45
二、BV001對於EGFR overexpression的A431有較強的毒殺性 45
三、BV001確實會抑制EGFR的表現及活性 46
四、BV001抑制EGFR表現及活性具有dose- dependent和time- dependent 46
六、BV001會抑制EGFR的promoter 47
七、BV001抑制STAT3表現和AKT的表現及活性 47
八、BV001誘導細胞走向凋亡 48
九、BV001會使細胞產生ROS 49
十、BV001會抑制ABCB1的表現 49
十一、抑制ERK活性使PC3細胞株對於BV001更加敏感 49
討論 51
圖表 55
附錄 77
參考文獻 83

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