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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 林亮音(Liang-In Lin) | |
| dc.contributor.author | Kao-Yu Chang | en |
| dc.contributor.author | 張高煜 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:45:08Z | - |
| dc.date.available | 2025-08-17 | |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-14 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78185 | - |
| dc.description.abstract | 在急性骨髓性白血病(Acute myeloid leukemia, AML)患者中，約有20~30%帶有FLT3基因突變，其中以FLT3之內部串聯重複(FLT3-ITD)最為常見，通常會使用酪胺酸激酶抑制劑治療，但最終因產生抗藥性而導致治療失敗；實驗室先前發現一個FDA核准用於固態腫瘤的酪胺酸激酶抑制劑cabozantinib，可選擇性抑制具有FLT3-ITD白血病細胞株。為了預防未來用於臨床白血病治療產生抗藥性的問題，實驗室建立具有cabozantinib抗性之MV4-11與Molm-13細胞，並研究產生抗藥性的機制。近年來文獻指出表觀遺傳的異常也是造成AML的原因，所以未來針對表觀遺傳的藥物可能是AML的替代用藥。因此，我們利用表觀遺傳調控物質的藥庫（SCREEN-WELL® Epigenetics library : BML-2836）篩選具發展潛力的藥物。 經藥庫篩選後，我們選擇出Trischosatin A (TSA, 廣泛型組蛋白去乙醯酶抑制劑)，及與TSA同為廣泛型組蛋白去乙醯酶抑制劑LBH589 (Panobinostat, FDA核准藥物)。TSA與LBH589對白血病細胞(MV4-11)及具有cabozantinib抗性之白血病細胞(MV4-11-XR)有良好的抑制效果，TSA之IC50在MV4-11與 MV4-11-XR細胞分別為59.93±15.9 nM、108.9±40.4 nM；而LBH589之IC50在MV4-11與MV4-11-XR細胞分別為1.80±0.24 nM、5.03±1.50 nM。我們發現TSA與LBH589可以停滯白血病細胞的細胞週期於G0/G1期，並抑制PI3K及MAPK訊息傳遞路徑且引發細胞凋亡以及造成DNA損傷。另外，TSA與LBH589可以抑制白血病細胞形成細胞群落的能力，並抑制自我更新相關基因及促進腫瘤抑制基因表現。最後評估TSA與LBH589合併使用cabozantinib的效果，發現TSA合併使用cabozantinib於MV4-11及MV4-11-XR細胞效果為加成、協同效果；LBH589合併使用cabozantinib於MV4-11及MV4-11-XR細胞效果均為協同效果。 總體而言，廣泛型組蛋白去乙醯酶抑制劑對MV4-11與MV4-11-XR細胞有良好的毒殺效果，因此未來可以評估使用組蛋白去乙醯酶抑制劑治療對具對TKI有抗藥性的AML，以期提高AML病人的生存率。 | zh_TW |
| dc.description.abstract | A total of 20-30% acute myeloid leukemia (AML) patients have mutations in the FLT3 (Fms-like tyrosine kinase 3) gene; among those, FLT3-internal tandem repeats (FLT3-ITD) were the most common. Patients with FLT3-ITD usually treated with tyrosine kinase inhibitors, but eventually the treatment fails due to drug resistance. In our laboratory previous studies, we found that the tyrosine kinase inhibitor cabozantinib approved by FDA for solid tumor treatment could selectively inhibit the proliferation of FLT3-ITD mutant AML cell lines. To evaluate the possibility of drug resistance in clinical leukemia treatment by using cabozantinib, we established cabozantinib-resistant cell lines MV4-11-XR and Molm13-XR from MV4-11 cells and Molm13 cells, respectively, to figure out the drug resistance mechanism. Many studies demonstrate that epigenetic changes participate in the pathogenesis of AML. As a consequence, epigenetically targeted therapies may be an ideal alternative strategy for AML treatment. In this study, we used a drug library (BML-2836) to select potential drugs for AML treatment. Following drug screening, two pan-HDAC inhibitors, trichostain A(TSA) and LBH589 were selected for further investigation. We found that TSA and LBH589 had good antileukemic effects on cabozantinib-sensitive leukemia cell MV4-11 cells and cabozantinib-resistant leukemia cell MV4-11-XR cells. IC50 for TSA against MV4-11 cells and MV4-11-XR cells were 59.93±15.9 nM and 108.9±40.4 nM, respectively; and IC50 for LBH589 against MV4-11 cells and MV4-11-XR cells were 1.80±0.24 nM and 5.03±1.50 nM, respectively. We also found that either TSA or LBH589 treatment could trigger G0/G1 cell cycle arrest and inhibit the PI3K and MAPK signaling pathways, subsequently accompanied by cell apoptosis and DNA damage. Moreover, both TSA and LBH589 inhibited colony forming ability and reduced the expression of self-renewal related genes and promoted the expression of tumor suppressor gene in both MV4-11 cells and MV4-11-XR cells. Finally, we evaluated the pan-HDAC inhibitor in combination with cabozantinib in MV4-11 cells and MV4-11-XR cells. Combination treatment of TSA and cabozantinib showed synergistic effect on MV4-11-XR cells and additive effect on MV4-11 cells. LBH589 plus cabozantinib showed synergistic effect on MV4-11 cells and MV4-11-XR cells. In this study, we demonstrated that pan-HDAC inhibitor exhibited promising antileukemic activity againt both MV4-11 cells and MV4-11-XR cells. Therefore, pan-HDAC inhibitor may be a clinically poteinal therapeutic agent in treating drug-resistance AML, improving the survival rates of patients. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:45:08Z (GMT). No. of bitstreams: 1 U0001-1308202022281100.pdf: 8008592 bytes, checksum: 7a143dc3139c1c56c4cddbb68c322040 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 口試委員會審定書 i 致謝 ii 摘要 iii Abstract v 目錄 vii 圖目錄 xi 補充資料目錄 xiii 表目錄 xiv 縮寫表 xv 第一章 前言 1 1.1. 急性骨髓性白血病簡介 1 1.1.1. 急性骨髓性白血病(Acute Myeloid Leukemia, AML) 1 1.1.2. AML之分類 1 1.1.3. 急性骨髓性白血病之治療 1 1.2. Histone deacetylase (HDAC)組蛋白去乙醯酶 4 1.2.1. 組蛋白(去)乙醯化 4 1.2.2. 非組蛋白類的蛋白(去)乙醯化 5 1.3. Histone deacetylase inhibitor (HDACi) 組蛋白去乙醯酶抑制劑 6 1.3.1. HDACi 治療AML的現況 6 1.3.2. Trichostatin A (TSA) 簡介 6 1.3.3. LBH589 (Panobinostat) 簡介 7 1.4. Fms-like tyrosine kinase 3 (FLT3) 7 1.4.1. FLT3簡介 7 1.4.2. FLT3突變 8 1.4.3. FLT3標靶藥物簡介 8 1.4.4. HDACi 治療FLT3基因突變的現況 10 第二章 研究目的 12 第三章 材料與方法 13 3.1. 材料 13 3.1.1. 細胞株 13 3.1.2. 儀器設備 13 3.1.3. 藥品 14 3.1.4. 使用的小分子藥物 16 3.1.5. 抗體 16 3.1.6. 試劑組 17 3.1.7. 藥品與試劑配製 17 3.2. 方法 19 3.2.1. 細胞培養 19 3.2.2. 細胞生長曲線(Cell proliferation curce) 19 3.2.3. 細胞抑殺試驗(MTS assay) 19 3.2.4. 流式細胞儀(Flow cytometry)分析 20 3.2.5. 細胞群落分析(Colony formation assay) 21 3.2.6. 細胞內蛋白質萃取 21 3.2.7. 蛋白質濃度定量 22 3.2.8. 西方墨點法 22 3.2.9. RNA萃取 23 3.2.10. 反轉錄聚合酶反應(reverse transcription) 23 3.2.11. 即時監控聚合酶連鎖反應(q-PCR) 24 3.2.12. 統計方法 24 3.2.13. 所使用到的軟體及網站 24 第四章 實驗結果 26 4.1. 從表觀遺傳物質藥庫(BML-2836)中篩選具發展潛力的藥物-Trichostatin A 26 4.2. TSA與LBH589對MV4-11及MV4-11-XR細胞的抑制效果 26 4.3. TSA與LBH589延遲MV4-11及MV4-11-XR細胞生長的速度 26 4.4. TSA與LBH589停滯MV4-11及MV4-11-XR細胞的細胞週期於G0/G1期 27 4.5. TSA與LBH589抑制MV4-11及MV4-11-XR細胞的PI3K/AKT及ERK1/2訊息傳遞路徑 27 4.6. TSA與LBH589引發MV4-11及MV4-11-XR細胞進行細胞凋亡 28 4.7. TSA與LBH589造成MV4-11及MV4-11-XR細胞的PARP切割及DNA損傷 28 4.8. TSA與LBH589抑制MV4-11及MV4-11-XR細胞群落形成的能力 29 4.9. TSA與LBH589抑制MV4-11及MV4-11-XR細胞自我更新相關基因的表現量，並促進腫瘤抑制基因KLF4表現 30 4.10. LBH589抑制MV4-11及MV4-11-XR細胞的DNA修復系統 32 4.11. 分析MLL-AF9細胞經藥物LBH589處理24小時後之基因表達差異性 33 4.12. TSA合併cabozantinib處理MV4-11細胞沒有協同作用 33 4.13. TSA合併cabozantinib處理MV4-11-XR細胞有協同作用 34 4.14. LBH589合併cabozantinib處理MV4-11細胞有協同作用 35 4.15. LBH589合併cabozantinib處理MV4-11-XR細胞有協同效果 35 第五章 討論 36 第六章 參考文獻 41 圖 52 補充資料 75 表 77 附圖 79 附表 87 | |
| dc.language.iso | zh-TW | |
| dc.subject | LBH589 | zh_TW |
| dc.subject | 急性骨髓性白血病 | zh_TW |
| dc.subject | FLT3-ITD | zh_TW |
| dc.subject | cabozantinib抗藥性 | zh_TW |
| dc.subject | 組蛋白去乙醯酶抑制劑 | zh_TW |
| dc.subject | Trichostatin A | zh_TW |
| dc.subject | Trichostatin A | en |
| dc.subject | LBH589 | en |
| dc.subject | AML | en |
| dc.subject | FLT3-ITD | en |
| dc.subject | Cabozantinib resistance | en |
| dc.subject | HDAC inhibitor | en |
| dc.title | 探討去乙醯基酶抑制劑Trichostatin A及LBH589對於白血病細胞之分子機制：著重在對cabozantinib具感受性及抗藥性之MV4-11細胞株 | zh_TW |
| dc.title | Study on the molecular mechanism of HDAC inhibitors -Trichostatin A and LBH589 in leukemia cells: focus on both cabozantinib-sensitive and -resistant MV4-11 cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 郭靜穎(Ching-Ying Kuo),顧雅真(Ya-Chen Ko),歐大諒(Da-Liang Ou),侯信安(Hsin-An Hou) | |
| dc.subject.keyword | 急性骨髓性白血病,FLT3-ITD,cabozantinib抗藥性,組蛋白去乙醯酶抑制劑,Trichostatin A,LBH589, | zh_TW |
| dc.subject.keyword | AML,FLT3-ITD,Cabozantinib resistance,HDAC inhibitor,Trichostatin A,LBH589, | en |
| dc.relation.page | 94 | |
| dc.identifier.doi | 10.6342/NTU202003337 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-15 | |
| 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 |
| dc.date.embargo-lift | 2025-08-17 | - |
| Appears in Collections: | 醫學檢驗暨生物技術學系 | |
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| U0001-1308202022281100.pdf Restricted Access | 7.82 MB | Adobe PDF |
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