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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37629完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 胡忠怡(Chung-Yi Hu) | |
| dc.contributor.author | Yi-Wen Kao | en |
| dc.contributor.author | 高意雯 | zh_TW |
| dc.date.accessioned | 2021-06-13T15:35:40Z | - |
| dc.date.available | 2013-10-07 | |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-10 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37629 | - |
| dc.description.abstract | 急性淋巴性白血病（Acute lymphoblastic leukemia, ALL）為造血系統不正常病變導致不成熟淋巴球異常增生的疾病；佔兒童癌症發生的第一位。目前兒童ALL的藥物治療成效良好，五年無事件存活率約達76~86%，不過帶有t(9;22)或MLL基因轉位的極高危險群（Very high risk, VHR）病人經密集高劑量化學治療後尚無法達到長時間的緩解。因此，發展對VHR-ALL病患更有效的治療療程或者新藥是ALL的重要研究課題。漆樹萃取物對苯二酚衍生物 HQ17(3)於先前曾經被研究發現有抗癌能力，且低濃度即對惡性骨髓性血癌細胞株HL-60有毒殺效果。
本研究於先驅測試中確定低濃度HQ17(3)對四株ALL細胞株即具有細胞毒性，乃選定帶有MLL-AF4基因轉位的RS4;11細胞株為標的，研究HQ17(3)造成VHR ALL細胞毒性之機轉。結果顯示HQ17(3)會誘導RS4;11細胞株中活性氧（ROS）的產生，破壞粒線體膜電位，硫胱胺酸蛋白酶（Caspase）活化，多二磷酸腺苷核糖聚合酶（PARP）被切割，細胞發生凋亡（Apoptosis）。加入泛硫胱胺酸蛋白酶抑制劑（Pan-caspase inhibnitor）雖然可以抑制HQ17(3)所誘發的caspase活性，但是卻無法抑制PARP切割與細胞死亡。抗氧化劑（Antioxidants, ROS scavengers）榖胱苷肽（GSH）和維生素C可以減緩HQ17(3)所誘導的ROS產生，減少細胞粒線體膜電位的變化，挽救細胞死亡。綜合本研究的實驗結果顯示ROS是HQ17(3)誘導RS4;11細胞死亡的主要原因之一；HQ17(3)雖亦造成caspase活化，但非HQ17(3)誘導RS4;11細胞死亡的原因。此外，本研究結果指出若可選擇性誘導細胞中ROS產生，可能有潛力發展輔助治療如MLL-AF4基因轉位的VHR ALL的策略。 | zh_TW |
| dc.description.abstract | Acute lymphoblastic leukemia (ALL), a haematopoietic malignant disorder of lymphoid cells, is the most prevalent childhood cancer. Although the rate of success in the treatment of childhood ALL has been improved with a 5-year event-free survival of 76-88%, patients succumbing very-high- risk (VHR) ALLs (those harboring t(9;22) or MLL rearrangements chromosomal abnormalities) display poor clinical outcomes even with intensive chemotherapies. Thus, more effective treatment protocols or new drugs are beneficial for these patients. HQ17(3)(10’(Z),13’(E),15’(E)-heptadecatrienyl-
hydroquinone), isolated from the sap of Rhus succedanea, had been reported to have anti-cancer activity, and low concentration of HQ17(3) showed cytotoxicity to the HL-60 myeloid leukemia cells. Our pilot screening confirmed HQ17(3) exhibited effective cytotoxic effect on four tested ALL cell lines. Thus, the RS4;11 cell line harboring MLL-AF4 gene translocation was chosen for the detailed investigation of the effects of HQ17(3) on VHR ALL cells. HQ17(3) induced reactive oxygen species (ROS) production in RS4;11 cells, and disrupted the mitochondrial membrane potential, activated caspase-3, and cleaved poly (ADP-ribose) polymerase (PARP). RS4;11 cells treated with HQ17(3) showed features of apoptotic cell death. Pan-caspase inhibitor could effectively inhibit HQ17(3)-induced caspase-3 activation, but could neither reduce HQ17(3)-induced PARP cleavage nor rescue cells from death. Antioxidants or ROS scavengers (GSH, vitamin C) attenuated HQ17(3)-induced ROS production, mitochondrial membrane potential lost, and cell death. These results indicated that oxidative stress associated with ROS production is one of the major mechanisms to cause HQ17(3)-induced RS4;11 cell death. In conclusion, HQ17(3) displayed significant anti-leukemic activity by inducing ROS and cell apoptotic death. These results further indicated that ROS-inducing agents might potentially augment the treatment for VHR ALL with t(4;11) translocation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T15:35:40Z (GMT). No. of bitstreams: 1 ntu-100-R98424029-1.pdf: 2872742 bytes, checksum: 240b8a65082596aa8922211b546b80bb (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 中文摘要 I
Abstract II 目錄 IV 圖目錄 VIII 附錄目錄 IX 第一章 緒論 1 第一節 急性淋巴性白血病 1 1.1 急性淋巴性白血病簡介 1 1.2 急性淋巴性白血病的症狀與診斷 2 1.3 急性淋巴性白血病的致病機轉與預後指標 3 1.4 急性淋巴性白血病的治療現況與成效 4 第二節 對苯二酚及其衍生物 6 2.1 對苯二酚相關文獻探討 6 2.2 對苯二酚衍生物─HQ17(3)相關文獻探討 9 第三節 細胞死亡 10 3.1 細胞死亡 10 3.2 細胞凋亡與硫胱胺酸蛋白酶依賴性細胞死亡（Apoptosis and caspase-dependent cell death） 11 3.3 非硫胱胺酸依賴性細胞死亡（Caspase-independent cell death） 14 第四節 活性氧族群 （Reactive oxygen species, ROS） 15 4.1 活性氧族群 15 4.2 活性氧族群（ROS）對細胞的傷害 16 4.3 細胞中的抗氧化系統 17 4.4 活性氧族群與細胞死亡 18 第五節 癌症的治療 19 5.1 癌症的發生與治療概況 19 5.2 急性淋巴性白血病的治療 21 第二章 研究目的與實驗設計 23 第一節 研究目的 23 1.1 研究目的 23 1.2 相關文獻回顧 23 第二節 實驗設計 24 第三章 材料與方法 25 第一節 實驗材料 25 1.1 細胞株 25 1.2 試藥/劑、抗體、儀器、耗材清單 25 1.3 各式溶液及其配方 28 1.3.1 細胞培養、繼代 28 1.3.2 流氏細胞儀相關實驗 29 1.3.3 萃取細胞蛋白質 29 1.3.4 鈉十二烷基硫酸鹽聚丙烯胺凝膠電泳與膠體轉漬 30 1.3.5 西方點墨法 32 第二節 實驗方法 33 2.1 解凍細胞、細胞培養及細胞計數 33 2.2 細胞活性測試及藥物IC50決定 33 2.3 細胞凋亡特徵與細胞膜完整性分析 34 2.4 細胞粒線體膜電位的測定 35 2.5 細胞內DNA含量分析（sub-G1） 35 2.6 細胞內caspase活性分析（西方點墨法） 36 2.6.1 蛋白質萃取 36 2.6.2 蛋白質定量、稀釋與電泳樣品準備 36 2.6.3 鈉十二烷基硫酸鹽聚丙烯胺凝膠電泳與膠體轉漬 37 2.6.4 阻斷非特異性結合與免疫染色 37 2.6.5 脫除反應與α-tubulin（internal control）免疫染色 38 2.6.6 定量分析計算方式 38 2.7 細胞內活性氧自由基的分析 38 2.8 統計分析 39 第四章 結果 40 第一節 HQ17(3)對急性淋巴性白血病細胞有細胞毒性 40 1.1 HQ17(3)能夠抑制急性淋巴性白血病細胞的生長及誘導死亡 40 1.2 HQ17(3)能夠抑制RS4;11細胞的生長及誘導死亡 40 第二節 HQ17(3)處理RS4;11細胞出現細胞凋亡特徵 41 2.1 HQ17(3)促使RS4;11細胞膜脂質外翻、細胞膜受損 41 2.3 HQ17(3)處理RS4;11細胞使DNA斷裂（sub-G1） 42 2.2 HQ17(3)處理RS4;11細胞使細胞粒線體膜電位發生改變 42 第三節 HQ17(3)促使RS4;11細胞死亡與caspase活化 43 3.1 HQ17(3)活化RS4;11細胞中的caspase 43 3.2 Pan-caspase inhibitor無法減少HQ17(3)所引起的細胞死亡 44 3.3 Pan-caspase inhibitor無法減緩PARP降解 45 第四節 HQ17(3)主要透過誘發ROS產生引起RS4;11細胞死亡 45 4.1 HQ17(3)會誘導RS4;11細胞中ROS產生 45 4.2 抗氧化劑可以減少HQ17(3)所引起的細胞死亡 46 4.3 抗氧化劑可以減緩HQ17(3)所誘導的ROS增加 46 4.4 抗氧化劑可以減緩HQ17(3)所造成的粒線體膜電位改變 47 第五章 討論 48 第六章 參考文獻 54 圖與表 64 附錄 82 | |
| dc.language.iso | zh-TW | |
| dc.subject | 急性淋巴性白血病 | zh_TW |
| dc.subject | 活性氧族群 | zh_TW |
| dc.subject | HQ17(3) | zh_TW |
| dc.subject | 硫胱胺酸蛋白酶 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | reactive oxygen species (ROS) | en |
| dc.subject | acute lymphoblastic leukemia (ALL) | en |
| dc.subject | apoptosis | en |
| dc.subject | caspase | en |
| dc.subject | HQ17(3) | en |
| dc.title | 分析天然植物對苯二酚衍生物HQ17(3)對帶有t(4;11)染色體轉位急性淋巴性白血病細胞株RS4;11的影響 | zh_TW |
| dc.title | The Effects of Botanical Alkyl Hydroquinone Derivative HQ17(3) on Acute Lymphoblastic Leukemia Cell Line, RS4;11 Harboring t(4;11) Chromosome Translocation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林淑萍(Shwu-Bin Lin),林亮音(Liang-In Lin) | |
| dc.subject.keyword | 急性淋巴性白血病,HQ17(3),細胞凋亡,硫胱胺酸蛋白酶,活性氧族群, | zh_TW |
| dc.subject.keyword | acute lymphoblastic leukemia (ALL),HQ17(3),apoptosis,caspase,reactive oxygen species (ROS), | en |
| dc.relation.page | 98 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-08-10 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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