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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/6165

    標題: 膽酸拮抗多重抗藥性及誘導細胞凋亡之效應與機制探討
    Effects and Mechanisms of Bile Acids on the Modula...
    作者: 蔡豐良
    Feng-liang Tsai
    貢獻者: 駱雨利
    關鍵字: Bcl-2 家族蛋白
    caspase 蛋白質水解酵素
    bile acids
    日期: 2005
    上傳時間: 2008-10-31 16:15:44 (UTC+8)
    摘要: 膽酸是極性膽固醇的衍生物為吸收飲食中的油脂和調控基因轉錄來控制膽固醇在體內平衡。依照化學結構式, 會有不同膽酸所表現出不同生物學上的作用.
    在這次的研究中,我們準備了人類結腸腺癌細胞株, Caco-2,和各種各樣不同的膽酸。我們挑選了不同疏水性與親水性的膽酸以評估這些膽酸當作多重抗藥性拮抗劑之可能性。細胞毒性分析已證實所使用的膽酸在250μM濃度範圍間是較無毒性的。將epirubicin 與膽酸合併使用後能明顯增加epirubicin 的細胞毒殺能力。我們也發現利用流式細胞分析儀技術,膽汁酸能顯著地增加epirubicin積存在Caco-2細胞內。我們發現這些拮抗劑會明顯抑制Caco-2 細胞上之MDR1和MRP1-6 mRNA的表現。尤其疏水性的膽汁酸與減少MDR1 和 MRP1-6 mRNA表現是有相關聯性。由luciferase assay實驗中去探討膽酸在Caco-2細胞內對調控hMDR1起始區域上游基因序列表現。另外,藉由螢光顯微鏡圖像、流式細胞分析儀分析和DNA片段化來分析這些膽酸是否會誘導細胞凋亡。進一步, 我們發現影響膽酸誘導細胞凋亡之分子機制,包括 p53, bax, caspase-3 和 caspase -9 mRNA表現增加和 bcl-2 mRNA 的mRNA表現減少,但是對caspase-8 mRNA表現不受影響。膽酸亦藉由影響bcl-2與bax相對量的表現,以調控細胞凋亡。
    結論, 我們將抗癌藥物與膽酸合併使用,能加強癌症化學法之療效。這些不具有毒性的膽酸不僅應用於多重抗藥性和細胞凋亡之調控機轉上,可降低全身之傷害並且提供更有效的對同屬於多重抗藥性範圍之藥物之生體可用率;而且對於癌症的預防作用有所助益。
    Bile acids are polar derivatives of cholesterol essential for the absorption of dietary lipids and regulating the transcription of genes that control cholesterol homeostasis. Depending on the nature of chemical structures, different bile acids exhibit distinct biological effects. In this study, the human colon adenocarcinoma cell line, Caco-2, was pretreated with various bile acids.
    We have chosen bile acids with different hydrophobicity and hydrophilicity to test their possibility as MDR antagonists. The cytotoxicity assay demonstrated that bile acids were non-toxic in the test concentrations ranging up to 250µM. Co-incubation of epirubicin with bile acids resulted in an increase in the cytotoxicity of epirubicin. These bile acids were shown to significantly enhance the intracellular accumulation of epirubicin in Caco-2 cells, as demonstrated by the flow cytometric study. These modulators were found to markedly inhibit mRNA expression levels of intestinal MDR1 and MRP1-6. The hydrophobicity of bile acids is correlated with the reduction in the mRNA expression levels of MDR1 and MRP1-6. Bile acids were also shown to negatively regulate the human MDR1 promoter region using the luciferase assay in Caco-2 cells. These bile acids were shown to induce apoptosis by fluorescence microscopic image, flow cytometric analysis, and DNA fragmentation assay. In addition, we found that bile acids-induced apoptotic cell deaths were accompanied by upregulation of p53, bax, caspase-3 and -9 mRNA expression and downregulation of bcl-2 mRNA expression with no effect on caspase-8 mRNA expression. These results suggest that the reduction of MDR1, MRPs and bcl-2 mRNA expression by bile acids possibly contributes to their cytotoxicity and apoptotic induction in this system.
    In conclusion, the combined use of anticancer drugs with bile acids may have significant implications in circumventing MDR of cancer chemotherapy. As MDR modulators in drug formulations, such non-toxic bile acids may reduce systemic side-effects and improve oral bioavailability of drugs in the MDR spectrum. The induction of apoptosis by bile acids may provide a pivotal mechanism for its cancer chemopreventive action.
    關聯: 校內校外均不公開
    Appears in Collections:[生物科技系(所)] 博碩士論文

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