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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 林亮音(Liang-In Lin) | |
dc.contributor.author | Yi-Ju Yang | en |
dc.contributor.author | 楊宜茹 | zh_TW |
dc.date.accessioned | 2021-06-16T06:30:22Z | - |
dc.date.available | 2017-08-01 | |
dc.date.copyright | 2014-10-09 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-08 | |
dc.identifier.citation | 1. Baccarani M, Dreyling M, Group EGW. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v165-167.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56854 | - |
dc.description.abstract | 大部分慢性骨髓性白血病(chronic myeloid leukemia, CML)的病人體內會存在第 9 對及第 22 對染色體轉位所產生的 BCR-ABL 融合蛋白,此融合蛋白會不斷啟動下游訊息傳遞蛋白造成細胞不斷增生、並且阻止細胞分化。因此,利用酪胺酸激酶抑制劑抑制BCR-ABL融合蛋白酪胺酸激酶的活性為治療辦法之一。Cabozantinib(XL184,N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide)為一多重酪酸胺激酶抑制劑,此藥物經美國FDA核准用於治療腎上腺髓質癌,建議每日用量與每日最大用量分別為140毫克與175毫克。根據藥物動力學研究顯示此藥物在每日用量175毫克時,人體血漿濃度可達2.8uM。本實驗室先前利用cabozantinib 進行實驗時,發現cabozantinib處理 K562 細胞放置數天後,細胞會變成紅色,故推論 cabozantinib 具有誘導K562細胞分化走向紅血球系列之能力,因此,我們主要目的是探討其中的機制。
首先,我們證實在小於血漿可達濃度之1uM cabozantinib處理K562細胞4天後,細胞會走向紅血球系列分化而非血小板系列。我們發現經1uM cabozantinib處理之K562細胞利用二胺基聯苯胺鹽酸(benzidine dihydrochloride)試驗與流式細胞儀,偵測細胞內血色素與細胞表面抗原CD71以及CD235a的表現量,證實經由cabozantinib處理之K562細胞,其紅血球系列分化相關之蛋白表現上升。而qRT-PCR 分析cabozantinib處理之K562細胞與紅血球分化相關之基因表現,例如:r-globin、transferrin receptor(TfR、CD71)、glycoforin A(GPA、CD235a)等基因,也呈現顯著上升的趨勢。我們發現cabozantinib可抑制K562細胞生長速率,而利用流式細胞儀分析細胞週期發現有細胞周期停滯的現象。進一步探討cabozantinib調控K562細胞分化之機制,我們發現cabozantinib處理K562細胞6小時後,細胞中BCR-ABL及其下游蛋白ERK, STAT5,AKT磷酸化之情形會隨著藥物濃度上升而下降。實驗結果亦顯示cabozantinib處理K562細胞48小時後,可造成c-myc蛋白表現下降,伴隨著p27蛋白表現上升。根據以上結果我們認為cabozantinib可藉由負調控AKT磷酸化使得p27蛋白表現增加,進而刺激K562細胞往紅血球系列分化。另外,我們也發現cabozantinib處理K562細胞6小時後,細胞中JNK及其下游分子磷酸化情形上升,並且利用JNK抑制劑可有效中和cabozantinib所刺激之分化現象,故我們認為cabozantinib亦可能透過JNK路徑調控K562細胞進行分化。 | zh_TW |
dc.description.abstract | Chronic myeloid leukemia (CML) is a pluripotent hematopoietic stem cell disease which arises from the bcr-abl oncogene. The Bcr-Abl oncoprotein, as a constitutively activated tyrosine kinase, could activate multiple signaling pathways for the malignant transformation. Therefore, specific inhibitors of tyrosine kinases are attractive therapeutic agents. Cabozantinib (XL184, N-(4-((6, 7-Dimethoxyquinolin-4-yl) oxy) phenyl)-N-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide), a multiple tyrosine kinase inhibitor, has recently been approved by US FDA for the treatment of medullary thyroid cancer (MTC). The recommended daily dose and the maximum-tolerated dose (MTD) of cabozantinib are 140mg and 175 mg, respectively. Pharmacokinetics study revealed that the steady-state plasma levels were 2.8μM when administrating MTC patients with 175mg daily. In our preliminary results revealed that treating K562 cells harboring bcr-abl oncogene with 1μM cabozantinib after a few days demonstrated an erythroid differentiation phenotype.
Treatment with plasma-reachable dose (1μM) of cabozantinib in K562 leukemia cells for 96 hrs induced erythroid differentiation but not megakaryocytic maturation. We observed a significant population of cells with cytological features of early erythroid differentiation and significantly increased benzidine-positive cells (up to 50%) accompanying with significant accumulation of γ-globin. Expression of transferrin receptor (TfR, CD71) and glycophorin A (GPA, CD235a), both well documented erythroid-specific gene, were induced 3 to 4-fold relative to untreated control cells. We found that cabozantinib could inhibit cell growth of K562 cells, and cell cycle analysis revealed that cabozantinib could also result in G0/G1 cell cycle arrest in K562 cells. Signaling pathway analysis revealed that cabozantinib could decrease phosphorylation of BCR-ABL, ERK, STAT5 and AKT at 6 hours in a dose-dependent manner. Further analysis revealed that cabozantinib treatment could decrease c-myc with a concomitant induction of p27 at 48 hours in a concentration- dependent manner. Taken together, we proposed that cabozantinib could induce K562 cell differentiation toward erythroid lineage through inhibiting PI3K/AKT pathway, of which, p27 was involved. In addition, we found that cabozantinib treatment could up-regulate phosphorylation of JNK and its downstream protein and JNK inhibitor could reduce the cabozantinib-induced erythroid differention on K562 cells. We considered that cabozantinib could also induce K562 cell differentiation toward erythroid lineage through JNK pathway. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T06:30:22Z (GMT). No. of bitstreams: 1 ntu-103-R01424005-1.pdf: 2829869 bytes, checksum: ed9fdc5d88a5a47a6cdf4dbe75c0e505 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 誌謝 I
目錄 II 圖目錄 IV 表目錄 IV 附圖目錄 V 附表目錄 V 縮寫表 VI 中文摘要 VII 英文摘要 IX 第一章 緒論 1 一.慢性骨髓性白血病(chronic myeloid leukemia, CML) 1 二.Cabozantinib (XL184) 4 三.分化 5 四.訊息傳遞 6 第二章 研究目的 7 第三章 材料與方法 8 一.材料 8 二.方法 15 第四章 實驗結果 21 一. Cabozantinib對K562細胞之影響 21 二. Cabozantinib刺激K562細胞分化為紅血球系列細胞 21 三. p38抑制劑中和cabozantinib刺激K562細胞分化之影響 23 四. Cabozantinib對K562細胞中p38 MAPK路徑之影響 24 五. Cabozantinib對K562細胞中BCR-ABL表現之影響 24 六. Cabozantinib對K562細胞週期之影響 24 七. Cabozantinib對K562細胞週期相關蛋白表現之影響 25 第五章 討論 27 第六章.結論 30 圖 31 表 59 參考文獻 60 附錄 67 一. 附圖 68 二. 附表 76 | |
dc.language.iso | zh-TW | |
dc.title | cabozantinib 誘導K562細胞株進行紅血球系列分化之機制的探討 | zh_TW |
dc.title | Study on the molecular mechanism of cabozantinib-induced erythroid differentiation of K562 erythroleukemia cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 胡忠怡(Chung-Yi Hu),郭遠燁(Yuan-Yeh Kuo),毆大諒(Da-Liang Ou),顧雅真(Ya-Chen Ko) | |
dc.subject.keyword | carbozantinib,紅血球系列分化,BCR-ABL融合蛋白, | zh_TW |
dc.subject.keyword | cabozantinib,erythroid differentiation,BCR-ABL fushion protein, | en |
dc.relation.page | 78 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-08 | |
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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