臺灣博碩士論文加值系統

化學治療是治療癌症常用且有效的療法，但是腫瘤細胞對抗癌藥物產生抗藥性是化學治療失敗的主要原因。而造成癌細胞多重抗藥性(multidrug resistance；MDR)的主因是細胞內某些酵素和蛋白質在量或功能上的改變，P-glycoprotein(P-gp)和multidrug resistance -associated protein(MRP)便是腫瘤細胞膜上與多重抗藥性有關的主要二種蛋白質。
我們利用三種乳癌細胞株MCF-7，對doxorubicin有抗藥性的細胞MCF-7/adr，對etoposide有抗藥性的細胞MCF-7/vp，來分析tryptanthrin的衍生物DQ150和EY083對抑制癌細胞多重抗藥性的影響。我們證明10-6M DQ150和EY083能降低MCF-7/adr細胞MDR1(轉錄P-gp)，glutathione S-transferase π (細胞內將藥物去活性的酵素)基因 mRNA的表現，且DQ150作用較EY083強；而在MCF-7/vp細胞中10-6M DQ150則能降低MRP1基因mRNA的表現。由西方墨點法分析蛋白質的表現，與mRNA的表現有正相關性。所以DQ150和EY083可能藉由改變與多重抗藥性有關物質表現量來抑制癌細胞多重抗藥性。
許多研究發現野生型p53可以藉由直接與轉錄因子作用而影響MDR1和MRP1基因的表現。我們的研究發現DQ150和EY083可抑制MCF-7/adr和MCF-7/vp細胞內p53的突變，增加細胞內野生型p53的比例，而抑制MDR1和MRP1基因的表現。
由gel mobility shift實驗觀察DQ150和EY083對MDR1基因、MRP1基因啟動子與轉錄因子結合能力的影響，發現EY083能干擾AP-1、SP-1與MDR1基因啟動子結合的能力，而抑制MDR1基因的表現，而DQ150則無。但是DQ150能藉由增加NF-κB/p65和c-Fos複合物與MDR1基因啟動子上CAAT區域結合能力，而負向控制MDR1基因的表現。此外，DQ150能干擾SP-1與MRP1基因啟動子結合的能力，而抑制MRP1基因的表現。
目前臨床上使用的多重抗藥性抑制劑多為P-gp的受質，與抗癌藥物競爭P-gp的結合位，但DQ150和EY083作用機制與傳統機制明顯不同，為逆轉癌細胞多重抗藥性的研究提供的新的方向。

Chemotherapy is a common and effective treatment for tumors. However, the resistance of tumor cells to anticancer agents remains a major cause of treatment failure in cancer patients. Increased expression in tumor cells of plasma membrane proteins such as the P-glycoprotein (P-gp) or the multidrug resistance-associated protein 1 (MRP1) is often associated with such multidrug resistance (MDR) phenotype. P-glycoprotein and MRP1 both belong to membrane transport proteins of the large ATP-binding cassette (ABC) superfamily but share less than 20% amino acid identity.
We have evaluated the tryptanthrin derivatives DQ150 and EY083 for their reversing activity against P-gp and MRP-mediated MDR in breast cancer cell lines MCF-7 and its counter parts, adriamycin-resistant MCF-7 (MCF-7/adr) and etoposide-resistant MCF-7 (MCF-7/vp). Using RT-PCR assay, 10-6M DQ150 is more efficient than 10-6M EY083 to decrease MDR1, glutathione S-transferase π (a drug detoxification enzyme) and MRP1 mRNA overexpression. When MCF-7/adr cells were treated with DQ150 at 10-6M for 5 days, we observed a large amount of reduction of P-gp and GSTπ protein in parallel with decreases in mRNA. In MCF-7/vp, MRP1 protein decreases when treated with 10-6M DQ150.
Many studies have provided evidence implicating complex formation for transcriptional regulation of the MDR1 and MRP1 gene promoters in human cancer cells. In addition, wild type p53 can modulate promoter activity of the human MDR1 and MRP1 genes. In MCF-7/adr cells, AP-1 and SP-1, interacting with MDR1 gene promoter, were affected by EY083 at 10-6M through the gel mobility shift assay, while it was not observed when treated with DQ150. However, DQ150 enhanced the NF-κB/p65 and c-Fos transcription factors interacting with the negatively regulatory CAAT region of the MDR1 gene promoter in MCF-7/adr.
On the other hand, DQ150 is more efficient than EY083 in the interfering with the interaction of SP-1 and MRP1 gene promoter in MCF-7/vp. The amount of mutant p53 decreased significantly when MCF-7/adr and MCF-7/vp were treated with DQ150 and EY083 at 10-6M. Take together, we conclude that different mechanisms may be involved in the inhibition of MDR1 expression by DQ150 and EY083, while these two compounds inhibit MRP1 expression through similar pathways

目錄
壹、緒論---------------------------------------------1
1. 前言
2. P-glycoprotein (P-gp)
3. Multidrug resistance-associated protein (MRP)
4. 拓樸異構酶(Topoisomerase)
4-1拓樸異構酶I (Topoisomerase I)
4-2拓樸異構酶II (Topoisomerase II)
5. Glutathione S-transferases及其相關酵素
6. 多重抗藥性的逆轉
貳、材料及方法-------------------------------------12
1. 培養基之製備
2. 細胞株的培養
3. 逆轉錄-聚合酶連鎖反應法(RT-PCR)
4. 西方點漬法(Western Blotting)
5. Rhodamine 123 Efflux assay
6. Gel Mobility Shift
7. 免疫沉澱法(Immunoprecipitation)
參、結果--------------------------------------------23
1. 由RT-PCR觀察MCF-7，MCF-7/adr及MCF-7/vp細胞中與MDR有關之基因mRNA的表現
2. 由RT-PCR實驗觀察DQ150或EY083對於MDR1 mRNA表現的影響
3. 利用西方墨點法來確定DQ150和EY083對P-glycoprotein之影響
4. 由RT-PCR實驗觀察DQ150或EY083對於GSTπ基因表現的影響
5. 利用西方墨點法來確定DQ150和EY083對GSTπ蛋白質表現之影響
6. 由RT-PCR實驗觀察DQ150或EY083對於multidrug resistance-associate protein 1 (MRP1)基因表現的影響
7. 利用西方墨點法來確定DQ150和EY083對multidrug resistance-associate protein 1(MRP1)表現之影響
8. 利用西方墨點法及免疫沉澱法觀察MCF-7、MCF-7/adr和MCF-7/vp 中p53的表現情形
9. 利用Gel Mobility Shift觀察DQ150和EY083干擾AP-1、SP-1與MDR1基因之啟動子的作用情形
10. 利用Gel Mobility Shift觀察DQ150和EY083對MDR1基因啟動子上CAAT區域與轉譯因子(NF-κB/p65和c-Fos)結合能力的影響
11. 利用Gel Mobility Shift觀察DQ150和EY083干擾SP-1與MRP1基因之啟動子的作用情形
肆、討論--------------------------------------------48
1. DQ150和EY083藉由改變與多重抗藥性有關物質表現量來抑制癌細胞多重抗藥性，可能與減少MDR1、GSTπ和MRP1的表現有關
2. DQ150和EY083可抑制p53的突變，增加細胞內野生型p53的比例，而抑制MDR1和MRP1基因的表現
3. DQ150和EY083能影響MDR1基因啟動子與轉錄因子結合，而抑制MDR1基因的表現
4. DQ150能干擾SP-1與MRP1基因啟動子結合的能力，而抑制MRP1基因的表現
伍、參考文獻----------------------------------------55

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