Quinacrine為治療瘧疾的藥物，亦具有抗風濕或作為胸膜硬化劑的功能。 目前雖已有報導指出Quinacrine具有抗癌之活性，但其對白血病細胞之效應及詳細機制仍未了解，因此本篇研究旨在探討Quinacrine誘導人類白血病K562細胞的死亡機制。 我們的實驗結果顯示Quinacrine會誘導K562細胞凋亡，並引發ROS含量提升進而導致p38 MAPK磷酸化、ERK去磷酸化與Bcl-2/Bcl-xL蛋白質表現量下降。 ERK的去磷酸化會抑制Bcl-xL mRNA表現量與其啟動子之冷光活性，而p38 MAPK磷酸化則造成Bcl-2蛋白質表現量下降。 Bcl-2與Bcl-xL表現量下降導致粒腺體膜電位流失以釋放細胞色素c來活化caspase-9/-3。 抑制p38 MAPK磷酸化或轉殖入持續活化的MEK1可分別阻斷Quinacrine誘導Bcl-2與Bcl-xL表現量下降的現象，而p38 MAPK抑制劑及回復ERK磷酸化亦可抑制Quinacrine誘發之粒腺體膜電位的流失。 綜合上述，我們的實驗結果顯示Quinacrine透過降低Bcl-xL與Bcl-2的表現量誘導人類白血病K562細胞凋亡。

Quinacrine, also known as mepacrine, is a drug applied on anti-protozoal and anti-rheumatic therapy. Moreover, quinacrine functioned as an intrapleural sclerosing agent as well. Although the anticancer activity of quinacrine has been reported, the detailed mechanism and effect on human leukemia cells remained elusive. In this study, we aimed to investigate the mechanism responsible for quinacrine-induced cell death of human leukemia K562 cells. It was found that quinacrine induced apoptosis of K562 cells. Quinacrine-induced ROS generation led to p38 MAPK phosphorylation, ERK inactivation and Bcl-2/Bcl-xL down-regulation. ERK inactivation led to reduce Bcl-xL mRNA level and promoter luciferase activity, while p38 MAPK phosphorylation promoted Bcl-2 down-regulation. Bcl-2/Bcl-xL down-regulation caused the loss of ΔΨm as well as the release of cytochrome c in quinacrine-treated cells, subsequently eliciting the caspase -9/-3 activation. Suppression of p38 MAPK phosphorylation or transfection of constitutively active MEK1 abolished quinacrine- induced Bcl-2 or Bcl-xL down-regulation, respectively. Consistently, SB202190 (p38 inhibitor) and restoration of ERK activation attenuated quinacrine-induced ΔΨm loss. Collectively, our data suggest that quinacrine induces apoptosis of human leukemia K562 cells via Bcl-xL and Bcl-2 down-regulation.

目錄

論文審定書 i
致謝 ii
摘要 iii
Abstract iv
目錄 v
圖次 vii
符號、縮寫說明 ix
第一章、前言 1
1.1 慢性骨髓性白血症 (Chronic Myeloid Leukemia, CML) 1
1.2 細胞凋亡 (Apoptosis) 3
1.3 Bcl-2家族 [B-cell lymphoma-2 (Bcl-2) family] 4
1.4 奎納克林 (Quinacrine) 5
第二章、研究方法與材料 7
2.1 實驗藥品 7
2.2 細胞培養 (Cell culture) 8
2.3 細胞藥物處理 (Drug treatment) 8
2.4 細胞相對存活率測試 (MTT assay) 8
2.5 細胞死亡型態分析 (Annexin V/PI double stain) 9
2.6 Caspase活性測試 (Caspase activity assay) 10
2.7 聚丙烯醯胺膠體電泳 (SDS-PAGE) 10
2.8 西方點墨法 (Western blot) 10
2.9 細胞內ROS濃度變化測定 (ROS generation test) 11
2.10 DNA 細胞轉殖 (DNA transfection) 11
2.11 粒腺體膜電位變化測定 (Mitochondria membrane potential test) 11
2.12 細胞色素c釋放分析 (Cytochrome c release assay) 12
2.13 RT-PCR 12
2.14 染色質免疫沉澱分析 [Chromatin Immunoprecipitation (ChIP) assays] 13
2.15 Promoter活性測試 (Promoter assay) 15
2.16 統計分析 (Statistical analysis) 16
第三章、結果 17
3.1 Quinacrine誘導K562細胞走向細胞凋亡 17
3.2 Quinacrine導致K562細胞內ROS含量提升 17
3.3 Quinacrine誘導p38磷酸化與ERK去磷酸化 18
3.4 Quinacrine導致細胞粒腺體膜電位下降 18
3.5 Quinacrine導致Bcl-xL與Bcl-2表現量下降、Bax轉移與細胞色素c釋放 19
3.6 Quicacrine透過ERK及p38 MAPK分別調控Bcl-xL及Bcl-2的蛋白表現 19
3.7 Quinacrine降低Bcl-2蛋白質的穩定性並抑制Bcl-xL mRNA的表現 19
3.8 Quinacrine透過抑制ERK活化進而抑制轉錄因子c-Jun的磷酸化 20
3.9 p-ERK藉由p-c-Jun調控Bcl-xL啟動子 20
第四章、討論 22
附圖 46
參考資料 47
會議發表著作 61

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