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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林亮音 | |
dc.contributor.author | Yen-Ling Lai | en |
dc.contributor.author | 賴彥伶 | zh_TW |
dc.date.accessioned | 2021-06-16T22:59:36Z | - |
dc.date.available | 2017-09-18 | |
dc.date.copyright | 2012-09-18 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-08 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64799 | - |
dc.description.abstract | PI3K/Akt訊息傳導路徑可以調控細胞的增生、凋亡,對於維持正常的細胞生理功能扮演著很重要的角色。在許多癌症的研究中發現PI3K/Akt訊息傳導路徑的不正常活化,並認為這樣的不正常活化可能是造成癌症的原因之一。在人類急性骨髓性白血病(Acute myeloid leukemia, AML)中,PI3K/Akt訊息傳導路徑亦有不正常活化的情形。為了針對這樣異常活化的訊息傳導路徑,有許多針對PI3K/Akt的抑制劑被研發出來,其中包含Akt抑制劑-MK-2206。為了研究MK-2206是否對於AML細胞具有毒殺作用及其作用機制,一開始先利用細胞抑殺試驗,發現MK-2206可以在低濃度下對AML細胞株達到毒殺作用(IC50 < 3 μM)而不會影響到正常的周邊血單核球細胞(IC50 > 18.8 μM),由此證明MK-2206的安全性。接下來利用流式細胞分析儀,發現在MK-2206處理下,會造成AML細胞停留在細胞週期中的G1期,並引發細胞凋亡。進一步利用西方墨點法分析跟細胞凋亡相關分子的表現,發現Myeloid cell leukemia 1 (Mcl-1)在MK-2206的處理下表現量會減少。Mcl-1是一個可以抵抗細胞凋亡的分子,進一步利用蛋白酶體抑制劑-MG-132及glycogen synthase kinase 3 (GSK3)抑制劑-氯化鋰,發現MK-2206在AML細胞株中所造成的Mcl-1減少的現象可能是經由GSK3引發後續經蛋白酶體降解Mcl-1所致。為了降低MK-2206的使用劑量,我們發現在使用低濃度MK-2206時,能有效降低化療藥物cytarabine的用量。Cytarabine是在臨床上常用來治療AML病人的化療藥品,但常有抗藥性產生或是治療無效的情況,因此,本實驗室建立出對cytarabine具有抗藥性的MV-4-11 AML細胞株(MV-4-11-R)。MV-4-11-R細胞的核質比較大、染色質較不緻密,且CD56表現量高(37.0% v.s. 22.6%),但HLA-DR抗原表現量低(2.3% v.s. 12.6%)。利用流式細胞分析儀,發現MV-4-11-R的細胞增生較慢(34.7% v.s. 48.4%)。使用Human Phospho-Kinase Array與西方墨點法發現MV-4-11-R之Akt磷酸化及ERK之磷酸化較高;進一步,合併使用Akt抑制劑(MK-2206)及MEK抑制劑(CI-1040)確實顯現具協同作用(CI值 < 1),而且無論是原本AML細胞株或是有抗藥性的細胞株都有此一效果。最後,我們以異體移植模式測試MK-2206與CI-1040合併使用的效果是否能有效抑制MV-4-11-P的生長,發現能有效縮減腫瘤的體積,但並不會影響到小鼠的體重,證明了此一用藥策略的可行性。 | zh_TW |
dc.description.abstract | Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway can regulate cell proliferation, apoptosis and play a critical role in maintaining normal cell function. It has been demonstrated that abnormal PI3K/Akt activation occurred in various cancers, including human acute myeloid leukemia (AML). As a result, many PI3K/Akt inhibitors were created to target this uncontrolled pathway, including MK-2206, an allosteric Akt inhibitor. We used MTS assay (cell proliferation assay) to evaluate the potency of MK-2206 on AML. MK-2206 was more cytotoxic to AML cell at low dose (IC50 < 3 μM) comparing to normal peripheral blood mononuclear cells (IC50 > 18.8 μM), thus demonstrated its biosercurity. Next, treatment of MK-2206 on AML cells resulted in cell cycle G1 arrest and induced apoptosis by using flow cytometry analysis. Further investigation on apoptosis-related molecules demonstrated myeloid cell leukemia 1 (Mcl-1) reduction when AML cells treated with MK-2206. Mcl-1 is an anti-apoptotic molecule. By using proteasome inhibitor MG-132 or glycogen synthase kinase 3 (GSK3) inhibitor lithium chloride, we found that Mcl-1 reduction by MK-2206 on AML cells resulted from proteasome degradation mediated by GSK3. To detect the efficacy of MK-2206 with plasma-reachable dose, 200 nM MK-2206 was used to evaluate the sensitivity of cytarabine. We found that combination of 200 nM and 75 nM cytarabine revealed similar effect of 150 nM cytarabine only. Cytarabine is a chemotherapeutic drug commonly used in AML treatment. However, no response or acquired resistance to cytarabine are frequently shown in AML patients. Thus, we established a cytarabine-resistant MV-4-11 (MV-4-11-R) cell line. The N/C ratio of MV-4-11-R was large and the chromatin of MV-4-11-R was less condensed compared with its parental cell (MV-4-11-P). There were more much more expression of CD56 and less expression of HLA-DR in MV-4-11-R compared with MV-4-11-P by using flow cytometry analysis. MV-4-11-R showed slower proliferation kinetics than MV-4-11-P. There was much more Akt and ERK phosphorylation in MV-4-11-R than MV-4-11-P by using Phospho-kinase Array analysis and western blot analysis. Subsequently, combination of Akt inhibitor MK-2206 and MEK inhibitor CI-1040 demonstrated significantly synergistic effect (CI < 1) in MV-4-11-R and its parental cell. As a result, we demonstrated that combination of MK-2206 and CI-1040 could inhibit proliferation of AML cells more effectively both in vitro and in vivo, representing a novel strategy to treat AML patients. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T22:59:36Z (GMT). No. of bitstreams: 1 ntu-101-R99424002-1.pdf: 3004295 bytes, checksum: a7145f3ba50283a831ff873c5eb2191d (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 目錄 I
圖目錄 VI 表目錄 VIII 縮寫表 IX 摘要 X Abstract XII 第一章 前言 1 1.1. PI3K/Akt訊息傳導路徑 1 1.1.1. Akt簡介 1 1.1.2. PI3K/Akt訊息傳導 1 1.1.3. 癌症的PI3K/Akt不正常活化的情況 1 1.2. 急性骨髓性白血病簡介及其與PI3K/Akt之關係 2 1.2.1. 急性骨髓性白血病(Acute myeloid leukemia, AML) 2 1.2.2. AML的PI3K/Akt活化情形 5 1.2.3. FLT3-ITD(fms-like tyrosine kinase 3-internal tandem duplication) 6 1.3. Akt抑制劑-MK-2206 7 1.4. MEK抑制劑-CI-1040 7 1.5. 細胞凋亡(Apoptosis) 8 1.5.1. 外源性路徑(Extrinsic pathway) 8 1.5.2. 內源性路徑(Intrinsic pathway) 8 1.6. Myeloid cell leukemia 1 (Mcl-1)分子 9 1.6.1. Mcl-1簡介 9 1.6.2. Mcl-1表現量調控機制 9 第二章 研究目的 11 第三章 材料與方法 12 3.1. 材料 12 3.1.1. 細胞 12 3.1.2. 儀器設備 12 3.1.3. 藥品 13 3.1.4. 抗體 15 3.1.5. 試劑組 15 3.1.6. 藥品與試劑配置 16 3.2. 方法 17 3.2.1. 細胞培養 17 3.2.2. 細胞抑殺試驗(MTS assay) 17 3.2.3. 周邊血單核球細胞(PBMC)分離 18 3.2.4. 細胞萃取物製備 18 3.2.5. 蛋白質定量 18 3.2.6. 西方墨點法 19 3.2.7. 細胞週期分析(Cell cycle analysis) 19 3.2.8. 細胞凋亡分析-Annexin V-PI雙染法 20 3.2.9. CFSE細胞增生試驗 20 3.2.10. RNA萃取 21 3.2.11. 反轉錄聚合酶連鎖反應(RT-PCR) 22 3.2.12. 即時監控聚合酶連鎖反應 22 3.2.13. 對cytarabine有抗藥性細胞之培養 23 3.2.14. 藥物加成試驗之作法及分析 23 3.2.15. Cytospin 23 3.2.16. 劉式染色 24 3.2.17. 白血球表面抗體螢光染色 24 3.2.18. Human Phospho-Kinase Array 24 3.2.19. 異種移植腫瘤模式 24 3.2.20. 統計方法 25 第四章 實驗結果 26 4.1. MK-2206對AML細胞的毒殺性 26 4.2. MK-2206對AML細胞的毒殺作用機制 27 4.2.1. 促使細胞停留在細胞週期中G1期 27 4.2.2. 引發細胞產生細胞凋亡 27 4.2.3. 對AML病人初代細胞影響 27 4.3. 利用西方墨點法分析發現MK-2206會降低Mcl-1蛋白表現 27 4.4. MK-2206處理可能引發GSK3活化,進一步造成Mcl-1由蛋白酶體降解 28 4.4.1. 利用MG-132處理反證Mcl-1因MK-2206減少現象是經由蛋白酶體降解所致 29 4.4.2. 利用LiCl處理反證Mcl-1因MK-2206減少現象是因GSK3造成 29 4.4.3. MK-2206的處理不影響Mcl-1的mRNA表現 29 4.5. 合併使用MK-2206與cytarabine能有效降低cytarabine毒殺AML細胞的濃度 30 4.6. MK2206在臨床上的應用性-對cytarabine有抗藥性的MV-4-11 30 4.6.1. 對cytarabine具有抗藥性的MV-4-11其細胞型態及表面抗原表現與母株細胞差異 30 4.6.2. 對cytarabine具有抗藥性的MV-4-11細胞增生速度較母株細胞慢 31 4.6.3. 對cytarabine有抗藥性的MV-4-11與母株細胞在磷酸酶表現的差異性 31 4.6.4. 合併使用MK-2206及CI-1040可對有抗藥性的MV-4-11產生協同作用 32 4.6.5. 合併使用MK-2206及CI-1040可對有抗藥性的MV-4-11引發細胞凋亡 32 4.7. 合併使用MK-2206及CI-1040能有效抑制MV-4-11細胞株的生長 33 4.7.1. 合併使用MK-2206與CI-1040可對MV-4-11細胞株產生協同作用 33 4.7.2. 合併使用MK-2206與CI-1040可以有效抑制MV-4-11腫瘤生長 34 第五章 討論 35 第六章 未來展望 41 第七章 參考文獻 42 圖 48 表 73 附圖 74 附表 76 | |
dc.language.iso | zh-TW | |
dc.title | 探討Akt抑制劑MK-2206對人類急性骨髓性白血病的分子作用機制及其在治療上的潛力 | zh_TW |
dc.title | Study on the Molecular Mechanism and Therapeutic Potential of MK-2206 in AML | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 簡銘賢,顧雅真,歐大諒,周文堅 | |
dc.subject.keyword | 急性骨髓性白血病,Akt,MK-2206,Cytarabine 抗藥性, | zh_TW |
dc.subject.keyword | Acute myeloid leukemia,Akt,MK-2206,Cytarabine resistance, | en |
dc.relation.page | 77 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-08 | |
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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ntu-101-1.pdf 目前未授權公開取用 | 2.93 MB | Adobe PDF |
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