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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 胡忠怡(Chung-Yi Hu) | |
| dc.contributor.author | Chia-Wei Chen | en |
| dc.contributor.author | 陳佳瑋 | zh_TW |
| dc.date.accessioned | 2021-05-13T08:36:22Z | - |
| dc.date.available | 2019-08-26 | |
| dc.date.available | 2021-05-13T08:36:22Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-13 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/3742 | - |
| dc.description.abstract | 好發於兒童的急性淋巴性白血病(acute lymphoblastic leukemia, ALL)為不成熟的B淋巴球和T淋巴球異常增生的一種血液癌症，造成ALL的原因有proto-oncogene不正常表現、染色體轉位(chromosome translocation)或多倍體(hyperdiploidy)等導致造血幹細胞(hematopoietic stem cell, HSC)或血液前驅細胞(hematopoietic progenitor cells, HPC)之異常增生、抗凋亡以及自我更新的能力。高危險群(high risk)的t(9;22) BCR-ABL+ precursor B-A LL在兒童ALL發生率約有3%，但在成人ALL卻超過25%，雖然在治療上採取最高劑量化療搭配tyrosine kinase inhibitors (如：Imatinib, IM)，但其預後仍差；而對第一線抗血癌藥物(如：glucocorticoid, Dexamethasone)的抗性是在T-ALL治療上常碰到的問題。因此，有必要針對這些高危險群(high risk)的ALL發展出新的治療策略。小分子10’(Z),13’(E),15’(E)-heptadecatrienylhydroquinone (HQ17(3))萃取自台灣漆樹(Rhus succedanea)的漆液，先前研究指出對於多種癌細胞具有選擇性毒性，但對周邊血液白血球則無明顯毒性，已知HQ17(3)能抑制DNA拓樸異構酶(DNA topoisomerase II)活性，在Huh7肝癌細胞中可造成氧化壓力引起細胞凋亡。 用低濃度(M)的HQ17(3)處理SUP-B15 (IM-refractory BCR-ABL+ B- A LL)或Jurkat (Dexamethasone-resistant T-ALL)細胞24小時即有顯著毒殺效果，HQ17(3)也會導致粒線體膜電位喪失並在Jurkat及SUP-B15細胞分別造成caspase-dependent，caspase- independent的細胞死亡。用低於IC50濃度的HQ17(3)能增加SUP-B15細胞對IM的敏感度，也能增加Dexamethasone對Jurkat細胞的抑制效果。
在SUP-B15細胞中，HQ17(3)引起細胞死亡之前有顯著的酸性胞器生成，顯示溶小體膜通透(lysosomal membrane permeabilization, LMP)或細胞自噬(autophagy)可能與細胞死亡相關。使用多種lysosome中cathepsins的抑制劑皆不能挽救HQ17(3)導致的死亡，說明與LMP相關的cathepsins溢出並非HQ17(3)導致細胞死亡的原因。HQ17(3)能造成外源性的EGFP-LC3融合蛋白的聚集，代表HQ17(3)能促使細胞產生autophagy。使用autophagy的抑制劑(Bafilomycin A1)以及利用shRNA抑制Beclin1 (autophagy發生的必要蛋白)的表現皆能降低HQ17(3)造成的死亡，autophagy誘導劑(Rapamycin)也可以減少HQ17(3)引起之細胞死亡。因此，HQ17(3)造成的死亡與autophagy相關。我們發現HQ17(3)在SUP-B15細胞迅速引起mTOR和NF-B的活化，顯示細胞遭受壓力。HQ17(3)造成內質網壓力進而導致eIF2磷酸化和ER chaperone-Grp78表現量的增加。推測HQ17(3)引起內質網壓力進而導致細胞發生autophagy和死亡。 本研究結果顯示HQ17(3)對高復發風險ALL細胞具有毒殺效果，且第一線用藥與HQ17(3)合併使用能增強對ALL細胞株的抑制作用，除了在Jurkat細胞引起典型的細胞凋亡，我們也發現HQ17(3)能對SUP-B15細胞造成內質網壓力和autophagy，而內質網壓力是否與HQ17(3)導致的autophagy和細胞死亡有關還需進一步探討。 | zh_TW |
| dc.description.abstract | Acute lymphoblastic leukemia (ALL), the most common cancer in childhood, is a neoplasm with uncontrolled proliferation of immature B- or T-lymphoid cells in hematopoietic system. Aberrant expression of proto-oncogene, chromosome translocation or hyperdiploidy make hematopoietic stem cell (HSC) or progenitor cells obtain ability of uncontrolled proliferation, anti-apoptosis and self-renewal and result in ALL development. High risk (HR) precursor B-ALL with t(9;22) BCR-ABL composed of 3% of childhood ALL and more than 25% of the adult ALL. It’s characterized by dismal clinical outcome, even treated with the highest dose chemotherapy combined with tyrosine kinase inhibitors (e.g. Imatinib, IM). Resistant to first-line drugs (e.g. glucocorticoid, Dexamethasone) is a common problem encountered in T-ALL treatment. Developing new therapeutic strategies for high risk ALL is necessary. The small natural molecule 10’(Z),13’(E),15’(E)- heptadecatrienyl hydroquinone (HQ17(3)) is extracted from the sap of the lacquer tree Rhus succedanea. HQ17(3) exerted selective cytotoxicity in various types of cancer cells, but did not reduce the viability of normal peripheral blood leukocytes. Introduction of HQ17(3) resulted in DNA topoisomerase II inhibition and oxidative stress production in Huh7 cell lines.
We found HQ17(3) had significant cytotoxic effect within 24 hours at micromolar concentration on HR SUP-B15 (IM-refractory BCR-ABL+ B-ALL) and Jurkat (Dexamethasone-resistant T-ALL) cell lines. HQ17(3) lead to loss of mitochondria membrane potential and caspase-dependent cell death in Jurkat cells. HQ17(3) induced caspase-independent cell death in SUP-B15 cells. Combination of sub-IC50 concentration of HQ17(3) sensitize SUP-B15 cells to Imatinib, and enhance the inhibitory effect of Dexamethasone on Jurkat cells. In SUP-B15 cells, HQ17(3) induced formation of acidic vesicles prior to cell death. The cause of HQ17(3)-induced cell death could not be attributed to cathepsins from lysosomal membrane permeabilization (LMP) because cathepsin inhibitors did not attenuate the cell death. HQ17(3) induced autophagy characterized by aggregation of ectopically expressed EGFP-LC3. Inhibition of autophagy by Bafilomycin A1 or knockdown the essential autophagy-related protein Beclin1 by shRNA could partially attenuate HQ17(3)-induced cell death. Autophagy induced by rapamycin also reduced the cytotoxic effect of HQ17(3). HQ17(3)-induced autophagy may be implicated cell death. Further, HQ17(3) treatment gave rise to early mTOR and NF-B activation, indicating induction of cell stress. HQ17(3) also induce ER stress as revealed by enhancement of eIF2 phosphorylation and up-regulation of ER chaperone Grp78. We speculate HQ17(3) may lead to ER stress and then result in autophagy and cell death. In summary, HQ17(3) is highly cytotoxic to high risk ALL cell lines (SUP-B15 and Jurkat), and combination of HQ17(3) with the first-line anti-leukemia drugs enhance the inhibitory effect on ALL cells. HQ17(3) also induced ER stress and autophagy in SUP-B15. Whether ER stress is essential for HQ17(3)-induced autophagy and cell death in BCR-ABL+ B-ALL cells await further investigation. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-13T08:36:22Z (GMT). No. of bitstreams: 1 ntu-105-R03424028-1.pdf: 4084579 bytes, checksum: f06bdca8722aa73d3be776fd27773f0c (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 致謝 ............................................................................................................................... I
中文摘要 .......................................................................................................................... II Abstract ........................................................................................................................... IV 縮寫表 ............................................................................................................................ VI 第一章 緒論 ..................................................................................................................... 1 一、 急性淋巴性白血病 ........................................................................................ 1 1、 急性淋巴性白血病的症狀 ........................................................................ 1 2、 急性淋巴性白血病的診斷 ........................................................................ 2 3、 急性淋巴性白血病的治療(risk-directed combined chemotherapies) ....... 3 4、 急性淋巴性白血病的不良預後因子 ........................................................ 4 二、 對苯二酚衍生物HQ17(3)簡介 ..................................................................... 5 1、 對苯二酚誘發caspase-dependent及caspase-independent細胞死亡模式 .................................................................................................................... 5 2、 對苯二酚衍生物HQ17(3) 相關文獻探討 ............................................... 6 三、 計畫性細胞死亡(Programmed cell death)..................................................... 7 1、 細胞凋亡(Apoptosis, type I cell death) ...................................................... 7 2、 細胞壞死(Necroptosis, type III cell death) .............................................. 11 3、 Lysosomal membrane permeabilization (LMP) ....................................... 11 4、 細胞自噬(Autophagy, Type II cell death) ................................................ 12 四、 Nuclear factor-kappa B (NF-κB) signaling pathway .................................... 14 五、 Unfolded protein response (UPR)-內質網壓力(ER stress) ......................... 15 六、 Preliminary data ............................................................................................ 17 第二章 研究目的與實驗設計 ....................................................................................... 18 一、 研究目的 ...................................................................................................... 18 1、 研究動機 .................................................................................................. 18 2、 研究目的 .................................................................................................. 19 二、 實驗設計 ...................................................................................................... 19 第三章 材料與方法 ....................................................................................................... 21 一、 實驗材料 ...................................................................................................... 21 1、 細胞株 ...................................................................................................... 21 2、 試藥/劑、抗體、儀器、耗材清單 ......................................................... 21 3、 各式溶液及其配方 .................................................................................. 27 (1) 細胞培養、繼代 .............................................................................. 27 (2) 流式細胞儀相關實驗 ...................................................................... 28 (3) 萃取細胞蛋白質 .............................................................................. 28 (4) 鈉十二烷基硫酸鹽聚丙烯胺凝膠電泳與膠體轉漬 ...................... 29 (5) 西方墨點法 ...................................................................................... 30 (6) 細胞存活/活性分析-Acid phosphatase assay (ACP assay) ............. 32 (7) 免疫螢光染色 .................................................................................. 32 二、 實驗方法 ...................................................................................................... 32 1、 解凍細胞、細胞培養及細胞計數 .......................................................... 32 2、 細胞存活分析 .......................................................................................... 33 (1) Acid phosphatase (ACP) assay ......................................................... 33 (2) 細胞膜磷脂質phosphatidylserine (PS)外翻與細胞膜完整性分析(Annexin V/PI) .................................................................................. 33 (3) 細胞粒線體膜電位的測定(DiOC6(3)染色) .................................... 34 3、 Autophagy的偵測 .................................................................................... 34 4、 Knockdown of Beclin1 ............................................................................. 35 5、 免疫螢光染色 .......................................................................................... 36 6、 RNA萃取與定量反轉錄聚合酶連鎖反應(qRT-PCR) ........................... 36 (1) RNA萃取 ......................................................................................... 36 (2) Quantitative reverse transcription polymerase chain reaction (qRT-PCR) ........................................................................................ 37 7、 西方墨點法 .............................................................................................. 37 (1) 蛋白質的萃取 .................................................................................. 37 (2) 蛋白質定量與電泳樣品準備 .......................................................... 38 (3) 鈉十二烷基硫酸鹽聚丙烯胺凝膠電泳與膠體轉漬 ...................... 38 (4) 阻斷非特異性結合與免疫染色 ...................................................... 39 8、 核質分離 .................................................................................................. 39 9、 X-box binding protein 1 (XBP1) mRNA splicing偵測 ........................... 40 第四章 結果 ................................................................................................................... 41 一、 HQ17(3)對ALL細胞株的毒殺能力 .......................................................... 41 1、 HQ17(3)對ALL細胞株具有毒性 .......................................................... 41 2、 HQ17(3)使T-ALL細胞株Jurkat細胞出現細胞凋亡特徵 ................... 41 (1) HQ17(3)促使Jurkat細胞膜PS外翻、細胞膜受損 ...................... 41 (2) HQ17(3)促使Jurkat細胞的粒線體膜電位喪失 ............................ 42 (3) HQ17(3)對Jurkat細胞引起caspase-dependent cell death ............. 42 二、 HQ17(3)與第一線淋巴性白血病藥物合併使用可增加對ALL細胞的抑制效果 ........................................................................................................ 43 1、 ALL細胞株對化療藥物有抗性 .............................................................. 43 (1) SUP-B15細胞對Imatinib有抗性 ................................................... 43 (2) Jurkat細胞對Dexamethasone有抗性 ............................................ 43 2、 第一線淋巴性白血病藥物與HQ17(3)合併使用可增加對ALL細胞的抑制效果 .................................................................................................. 44 (1) IM與HQ17(3)合併處理能增強對SUP-B15細胞的抑制效果 .... 44 (2) Dex與HQ17(3)合併處理能增強對Jurkat細胞的抑制效果 ........ 44 三、 HQ17(3)誘使SUP-15細胞死亡的effector ................................................ 44 1、 Lysosome中的proteases不是HQ17(3)在SUP-B15細胞中引起死亡的effector ..................................................................................................... 45 2、 HQ17(3)引起Autophagy ......................................................................... 45 3、 Autophagy參與HQ17(3)引起的細胞死亡 ............................................ 46 四、 HQ17(3)造成細胞壓力 ................................................................................ 47 五、 HQ17(3)造成內質網壓力(ER stess)............................................................ 48 六、 HQ17(3)造成DNA斷裂可能由Apoptosis-inducing factor (AIF)造成 .... 48 第五章 討論 ................................................................................................................... 50 圖與表 ............................................................................................................................. 68 附錄 ............................................................................................................................ 85 | |
| dc.language.iso | zh-TW | |
| dc.title | 分析植物對苯二酚衍生物HQ17(3)對急性淋巴性白血病細胞株的抑制作用 | zh_TW |
| dc.title | Inhibitory Effects of The Botanical Alkyl Hydroquinone Derivative HQ17(3) on Acute Lymphoblastic Leukemia Cell Lines | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林亮音,歐大諒,郭遠燁 | |
| dc.subject.keyword | 急性淋巴性白血病,細胞自噬,HQ17(3),內質網壓力, | zh_TW |
| dc.subject.keyword | ALL,autophagy,HQ17(3),ER stress, | en |
| dc.relation.page | 97 | |
| dc.identifier.doi | 10.6342/NTU201602460 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2016-08-15 | |
| 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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