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系統識別號 U0026-2407201221494900
論文名稱(中文) 前列腺素E2受體致效劑對DNA毀損藥物誘導骨髓性血癌細胞株細胞死亡的作用
論文名稱(英文) The Effect of PGE2 Receptor Agonists on DNA-damaging Agents Induced Cell Death in Myeloid Leukemia Cell Lines
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 100
學期 2
出版年 101
研究生(中文) 謝瑢
研究生(英文) Jung Hsieh
學號 S26991102
學位類別 碩士
語文別 英文
論文頁數 82頁
口試委員 指導教授-簡偉明
口試委員-陳清玉
口試委員-錢偉鈞
中文關鍵字 抗藥性  骨髓性白血病  前列腺素E2  EP受體  DNA毀損藥 
英文關鍵字 drug resistance  myeloid leukemia cells  PGE2  EP receptor  DNA damage drug 
學科別分類
中文摘要 抗藥性是骨髓性白血病(Myeloid Leukemia)治療後復發的最大問題,急性骨髓性白血病(AML)一旦復發有約70%的病人有抗藥性,而90%對藥物無效的慢性骨髓性白血病(CML)病人也是因為抗藥性的產生,為了解決骨髓性白血病的抗藥性,抗藥性相關的機轉是亟欲被探討的。
先前的研究發現,預後不佳的AML病人體內的cAMP濃度偏高,而HL-60 AML細胞株的研究中也發現cAMP可以保護細胞不受NO毒殺。cAMP作為一個第二訊息傳遞分子主要受到其他上游調控,例如:腺苷(adenosine)、腎上腺素(adrenaline)、前列腺素E2 (prostaglandin E2,PGE2)等。其中PGE2是生物體內重要的自泌素,藉由與EP受體作用維持正常的生理狀況,目前也發現它可以調控癌細胞的增生及凋亡。生物體內主要有四種EP受體:EP1、EP2、EP3、EP4,皆為G 蛋白偶聯受體,其中EP2和EP4會活化Gs蛋白增加下游因子cAMP,再透過PKA、PI3K等分子產生作用,EP3則活化Gi蛋白負向調控cAMP,而EP1是藉Gq調控體內的鈣離子。
本篇研究選用HL-60 AML細胞株及K562 CML細胞株,在DNA毀損藥處理的情況下,比較分別投與或不投與各種PGE2受體致效劑,對細胞的影響,利用PI (Propidium iodide)染DNA後再用流式細胞儀分析細胞周期和細胞凋亡。結果發現在HL-60 AML細胞中,僅有EP2受體致效劑butaprost可以減少doxorubicin、etoposide和cisplatin所造成的細胞凋亡,而進一步分析細胞周期的變化,發現butaprost可能是藉由引發G0/G1停滯而達到此結果。細胞存活率的實驗也發現butaprost可以回復DNA毀損藥造成的細胞生長抑制。但對化療藥較具抗性的K562 CML細胞株進行相同的實驗,卻看不到類似的現象可能是AML和CML致病訊息的差異所致。
總括本篇結果,發現EP2受體制效劑可能可以藉由調控下游因子cAMP等訊息路徑來保護HL-60細胞不受DNA毀損類化療藥的毒殺,此結果或許能為解決AML抗藥性提供一個的新的思考方向。
英文摘要 Drug resistance is an increasing problem in relapse and bad prognosis in myeloid leukemia treatment. In previous studies, the high cyclic AMP (cAMP) level in acute myeloid leukemia (AML) patients seems to be associated with the bad prognosis. In the HL-60 AML cell study, activation of cAMP reduced the NO-induced cell death. Since cAMP is a second messenger in human body, there must be an endogenous ligand to regulate it.
Prostaglandin E2 (PGE2 ), one of the most important upstream ligands regulate cAMP, is also known to promote proliferation and prevent apoptosis in many cancer cells. In other study, it was shown that PGE2 plays an important role on proliferation, differentiation and tumorgenesis in leukemia cells, while inhibiting PGE2 expression by COX-2 inhibitor was shown to suppress proliferation and increase apoptosis in human leukemia cell lines.
There are four subtype receptors for PGE2: EP1, EP2, EP3 and EP4 receptors. They are in the family of G-protein couple receptors. The EP1 receptor is known to activate Ca2+ signaling. And the EP2 and EP4 receptors are coupled with Gs protein and increase intracellular cAMP levels. On the other hand, EP3 is coupled with Gi protein to reduce intracellular cAMP levels. For these reasons, I aimed to investigate whether EP receptor agonists will prevent cell death from DNA damage drugs in HL-60 AML and K562 CML cell lines.
The cell cycle and cell death changed in different treatments are observed by PI stain with flow cytometry. This data showed that only pretreatment with EP2 receptor agonist reduce doxorubicin-induced cell death in HL-60 cells, but not the other EP receptor agonists. The similar results were found in both etoposide and cisplatin treatments. The data also implied EP2 receptor agonist may protect cells against death through G0/G1 arrest. Moreover, the EP2 receptor agonist also reversed the cell viability inhibition, which induced by DNA damage drugs. However, those results cannot found in K562 CML cells. The different oncogenic pathways in this two cell lines may contribute to the different response on DNA damage drugs.
In summary, EP2 receptor agonist may protect HL-60 AML cells against the death induced by DNA damage drugs through G0/G1 arrest. And EP2 receptor agonist can also reduce the cell viability inhibition induced by DNA damage drugs. Those results may provide a new direction to solve drug resistance in AML treatment.
論文目次 考試合格證明....................................................................................................I
中文摘
要..........................................................................................................II
Abstract...........................................................................................................IV
誌謝.................................................................................................................VI
Contents.........................................................................................................VII
Table contents...............................................................................................VIII
Figure contents................................................................................................IX
List of Abbreviations.......................................................................................XI

Introduction.......................................................................................................1
Materials and Methods....................................................................................18
Results.............................................................................................................24
Conclusion and Discussions............................................................................32
Reference.........................................................................................................39
Appendix.........................................................................................................57
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