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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳燕惠 | |
| dc.contributor.author | Yeh-Ssu Lin | en |
| dc.contributor.author | 林曄思 | zh_TW |
| dc.date.accessioned | 2021-06-15T02:28:29Z | - |
| dc.date.available | 2014-09-15 | |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-08-17 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/43782 | - |
| dc.description.abstract | 多重抗藥性（mutidrug resistance）是癌症化學治療常見的問題，經常伴隨某些酵素或細胞生物標記表現量或功能上的改變，如P-gp（P-glycoprotein），MRP（mutidrug resistance-releated protein），topoisomerase或glutathione等。我們利用乳癌細胞株MCF-7/WT和具有對adriamycin類抗癌藥有抗藥性的細胞株MCF-7/ADR，研究在此兩種細胞株表現量有差異的酵素或蛋白質，包括ER-α (estrogen receptor α)、ER-β (estrogen receptorβ)、PR (progestrone receptor)、VEGF（vascular endothelial growth factor）、HIF-1α ( hypoxia-inducible factor-1α ) 、FoxO1（forkhead box-containing protein，O subfamily）、C/EBP β（CCAAT/enhancer-binding protein β）、CtBP1(C-terminal binding protein 1)、dicer 1、argonaute 2、PIM-1以及PKc α (protein kinase c α)，藉以深入研究多重抗藥性的機制。
色胺酮(tryptanthrin)是一種吲哚類衍生物，併用tryptanthrin和doxorubicin可使MCF-7/ADR細胞對doxorubicin的敏感性上升、doxorubicin IC50值大幅降低。 我們以tryptanthrin為工具，利用聚合酶連鎖反應法(PCR)、即時定量-聚合酶連鎖反應法 (real-time PCR)以及西方墨點法(Western blot) 觀察MCF-7/WT和MCF-7ADR細胞在加了10-6 M tryptanthrin五天後，對前述目標蛋白質的影響。在篩選的過程中雖然沒有發現新的方向來解釋MCF-7/ADR細胞抗藥性產生的原因，但發現tryptanthrin具有抑制核蛋白受體表現的能力。MCF-7/WT細胞加入tryptanthrin後，ER-α蛋白的表現下降了一半。並且進一步藉由EMSA實驗證實tryptanthrin會影響ER-α啟動子上IEF-1區域與SP1家族蛋白的鍵結，暗示著tryptanthrin抑制ER-α基因的表現可能是經由減少ER-α啟動子與SP1家族蛋白的鍵結。MCF-7/WT細胞的PR基因比ER-α基因更快受到tryptanthrin的抑制，但文獻報導PR基因位於ER-α基因下游，暗示著PR基因受到tryptanthrin的影響可能不是經由ER-α基因的改變。另外還藉由siRNA抑制MCF-/WT細胞的ER-α基因，發現MDR1基因並沒有因此而表現，所以tryptanthrin抑制ER-α基因的表現和MCF-7/ADR細胞表現MDR1基因並沒有直接相關。 | zh_TW |
| dc.description.abstract | Multidrug resistance (MDR), the resistance of tumor cells to anticancer agents, remains a major cause of treatment failure for cancer patients. MDR usually occurs with alteration of function and expression of some proteins and enzymes, for example P-gp (P-glycoprotein), MRP (multidrug resistance-related protein), topoisomerase and glutathione. Recently, the genes which show differential expressions in MCF-7/WT and its doxorubicin-resistant counterpart MCF-7/ADR include ER-α (estrogen receptor α), ER-β (estrogen receptor β), PR (progesterone receptor), VEGF（vascular endothelial growth factor）, HIF-1α ( hypoxia-inducible factor-1α ) , FoxO1（forkhead box-containing protein，O subfamily）, C/EBP β（CCAAT/enhancer-binding protein β）, CtBP1(C-terminal binding protein 1), dicer 1, argonaute 2, PIM-1 and PKc α (protein kinase c α).
Our lab previously demonstrated that tryptanthrin could reverse the resistance to doxorubicin in MCF-7/ADR. In order to extensively understand the mechanisms of multidrug resistance, MCF-7/WT and MCF-7/ADR were treated with trptanthrin to examine the changes in expression of the above genes in this study, using RT-PCR, realtime-PCR and Western blot. Results show that tryptanthrin suppresses the expression of nuclear receptor genes in MCF-7/WT. The expression of ER-α is 50％ down. Furthermore, the binding of SP1 family proteins to ER-α promoter site IEF-1 decreases upon tryptanthrin treatment. In mRNA level, tryptanthrin inhibits the expression of PR prior to the expression of ER-α. As PR is downstream protein of ER-α, it seems that tryptanthrin acts on PR and ER-α via different pathways. When ER-α expression was knockdowned by siRNA in MCF-7/WT, the expression of MDR1 gene did not induced, suggesting the decrease in ER-α was not related to MDR1 gene expression in MCF-7/ADR. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T02:28:29Z (GMT). No. of bitstreams: 1 ntu-98-R96423017-1.pdf: 1368990 bytes, checksum: a640ee2ac104ff581926ae54403b6564 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 目錄
中文摘要………………………………………………………………………………i 英文摘要………………………………………………………………………...……iii 目錄……………………………………………………………………………………v 圖表目錄…………………………………………………………………………….viii 縮寫對照表…………………………………………………………………………....x 壹、 緒論……………………………………………………………………………....1 1.1 MCF-7/WT和MCF-7/ADR細胞的特性和差別…………….………….....1 1.2雌激素受體和黃體酮受體在乳癌細胞的表現和影響………….………....1 1.3雌激素受體 α啟動子位置受到數個轉錄因子的調控………….…………3 1.4 PKc α 在乳癌細胞裡扮演許多重要的調控角色…………..……………...4 1.5 MCF-7/WT和MCF-7/ADR細胞受到VEGF、HIF-1α和MMP 9影響，表現不同程度的血管新生(angiogenesis) ……………………………………..4 1.6 FoxO1、C/EBP β和CtBP1蛋白對MDR1基因啟動子的影響…….………6 1.7 Dicer1、Argonaute2和MCF-7細胞抗藥性的關係……………………...….6 1.8 色胺酮具有逆轉MCF-7/ADR細胞所產生的抗藥性…..…………….7 1.9 利用色胺酮來研究MCF-7/WT轉變成MCF-7/ADR細胞的可能機制………………………………………………………………………….8 貳、 材料及方法………………………………………………………………………9 2.1 實驗儀器………………………………………..……………………………9 2.2 實驗材料…………………………………………..…………………………9 2.3 緩衝液及培養液之製備………………………..…………………………..12 2.4 實驗方法…………………………………………………………………..14 一、 培養基之製備………………………………………………………...14 二、 細胞株的培養………………………………………………………...15 三、 逆轉錄-聚合酶連鎖反應法( RT-PCR ) ……………………………..15 四、 即時定量-聚合酶連鎖反應法( real-time PCR ) …………………….16 五、 西方墨點法 ( Western blot ) ………………………………………...16 六、 EMSA (Electrophoresis mobility shift assay) ………………………..18 七、 SiRNA ( transient transferction ) ……………………………………..19 2.5 統計檢定………………………………………………………………...19 參、 實驗結果………………………………………………………………………..20 3.1 利用RT-PCR觀察tryptanthrin對ER-α、ER-β、PR、HIF-1α、VEGF、 MMP 9、PKc α、PIM-1、Dicer1、Ago2、FoxO1、C/EBP β和CtBP1基因的影響…………………………………………………………………....20 3.2 利用real-time PCR和Western blot去觀察tryptanthrin對MCF-7/WT和MCF-7/ADR細胞中，ER-α、ER-β、PR和PKc α基因的影響…………………………………………………………………………....22 3.3 加入tryptanthrin後MCF-7/WT細胞 PR mRNA的表現先減少， ER-α mRNA的表現才隨著降低………………………………………………....23 3.4 Tryptanthrin會影響ER-α啟動子IEF-1上SP1家族蛋白的鍵結………23 3.5 Tryptanthrin降低MCF-7/ADR細胞MDR1基因的表現，和ER-α的改變沒有直接關…………………………………..…………………………....24 3.6 Tryptanthrin會促進MCF-7/WT細胞的HIF-1α、VEGF和MMP 9等和腫瘤血管增生相關基因的表現……………………………………………....24 肆、 討論……………………………………………………………………………..26 4.1 Tryptanthrin對ER-α、ER-β、PR、HIF-1α、VEGF、MMP 9、PKc α、PIM-1、Dicer1、Ago2、FoxO1、C/EBP β和CtBP1基因的影響……………26 4.2 Tryptanthrin會抑制MCF-7/WT細胞ER-α基因的表現是經由減少SP1和AP2家族蛋白分別與ER-α啟動子上IEF-1區域和ER-α的3`非轉錄區域ERF-1的鍵結……………….……………….……………………………...28 4.3 Tryptanthrin會先抑制PR mRNA的表現之後，ER-α mRNA的表現才會在隨後降低…………………………………………………………………29 4.4 MCF-7/ADR細胞產生抗藥性的機制和ER-α基因的減少並沒有直接相關……………………………………………………………………………29 伍、結論…………………………………………………………………………..…30 陸、圖表………………………………………………………………………..……31 柒、參考文獻…………………………………………………………………..……52 附錄一、色胺酮之化學結構…………………………………………………..……60 | |
| dc.language.iso | zh-TW | |
| dc.subject | 抗藥性 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | 色胺酮 | zh_TW |
| dc.subject | PR | zh_TW |
| dc.subject | MCF-7/WT | zh_TW |
| dc.subject | ER-α | zh_TW |
| dc.subject | tryptanthrin | en |
| dc.subject | breast cancer | en |
| dc.subject | ER-α | en |
| dc.subject | MCF-7/WT | en |
| dc.subject | multidrug resistance | en |
| dc.subject | PR | en |
| dc.title | 色胺酮在乳癌细胞MCF-7的作用 | zh_TW |
| dc.title | The Effect of Tryptanthrin in MCF-7 Breast Cancer Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許麗卿,陳擇銘 | |
| dc.subject.keyword | 抗藥性,色胺酮,乳癌,ER-α,PR,MCF-7/WT, | zh_TW |
| dc.subject.keyword | breast cancer,ER-α,MCF-7/WT,multidrug resistance,PR,tryptanthrin, | en |
| dc.relation.page | 60 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-08-17 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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