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首页> 外文学位 >MicroRNA regulation of anthracycline drug resistance in leukemia through miR-221, miR-222, miR-26a, and miR-21.
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MicroRNA regulation of anthracycline drug resistance in leukemia through miR-221, miR-222, miR-26a, and miR-21.

机译：通过miR-221，miR-222，miR-26a和miR-21对白血病中蒽环类药物耐药性的MicroRNA调节。

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摘要

Drug resistance takes many forms including decreased drug influx, increased metabolism by cytochrome P450 enzymes, and increased drug efflux, with P-gp mediated efflux of chemotherapeutic drugs being one of the most common. Anthracyclines, which are prevalently used drugs in cancer treatment, each contain a sugar moiety which is important in the drug's efficacy. Through modification of the sugar moiety we propose to both overcome P-gp related drug resistance and determine if alternative forms of drug resistance exist. Through methods of chemical biology we created 25 derivatives of daunorubicin with varying alterations to the sugar structure. We showed that the activity of the DNR can be more or less effective through these changes. Molecular docking showed that changing the amino group to an azido group or conversion of a monosaccharide to a disaccharide made binding to P-gp less favorable. Further docking studies showed that alteration of the sugar group could change DNR's specificity from a topoisomerase2 poison to a topoisomerase1 poison. Additionally sugar modification will change the specificity of the compound during DNA interchelation resulting in changes to microRNA levels. The combination of these studies provides us with a better understanding of the critical elements of the sugar moiety of anthracyclines, and provides us with a starting point to design more effective anticancer drugs.; From the 25 derivatives created using chemical biology, we identified two new anthracycline analogs (ADNR, ADNR3) which avert P-gp binding and overcome P-gp-mediated drug resistance. To study other novel mechanisms for drug resistance in leukemia independent of P-gp, doxorubicin, daunorubicin, ADNR, and ADNR3 were used to induce a new type of drug resistance, which was associated with microRNA regulation.; A microRNA microarray assay demonstrated that 5 to 15 microRNAs were up-regulated by at least 1.5-fold, and 2 to 122 microRNAs were down-regulated by 2 to 4852-fold in drug induced resistant leukemia cells by doxorubicin (DOX), daunorubicin (DNR), ADNR, and ADNR3. miR-221 and miR-222 were consistently down-regulated by 2 to 15-fold in all four drug induced resistant cells. Low levels of miR-221 and miR-222 in these drug-resistant cells up-regulate 4 to 8-fold expression of Kit protein, a receptor tyrosine kinase for cell survival. Transfection of miR-221 and miR-222 in four drug-resistant cells regained drug sensitivity. This indicates that down-regulation of miR-221 and miR-222 and subsequent up-regulation of Kit provides a novel mechanism for drug resistance in leukemia. Application of microRNA may provide a novel tool to battle drug resistance in leukemia chemotherapy.; Through real time RT-PCR we also determined that miR-26a was down-regulated by 1.49 to 3.60-fold in doxorubicin and daunorubicin resistant K562 leukemia cells. These low levels of miR-26a in doxorubicin and daunorubicin resistant cells up-regulate the expression of cdk6 by 3.65 and 4.42-fold. The miR-26a/cdk6 regulation mechanism was confirmed through transfection of miR-26a into drug resistant cells where cdk6 expression levels were knocked out, and drug sensitivity was restored. The IC50 value for doxorubicin was decreased by 11.01-fold, and the IC50 value of daunorubicin was decreased by 12.97-fold. This indicates that down-regulation of miR-26a and subsequent up-regulation of cdk6 provides a novel mechanism for drug resistance. The regulation of cdk6 by miR-26a opens the door for further research into the regulation of cell cycle proteins by microRNA. This gives a better understanding into the role microRNA plays in drug resistance, and allows for application of microRNA as a tool to help battle drug resistance in leukemia.; Anthracycline treatment also up-regulates microRNA, including miR-21 which was up-regulated by 2.51 to 6.51-fold in the four drug resistant cell lines. miR-21 is of importance due to its regulation of the tumor suppressor, PTEN. This upre
机译：耐药性有多种形式，包括减少药物流入，通过细胞色素P450酶增加新陈代谢和增加药物流出，其中P-gp介导的化学治疗药物流出是最常见的一种。蒽环类药物（通常在癌症治疗中使用的药物）每个都含有一个糖部分，这对药物的疗效至关重要。通过修饰糖部分，我们建议既克服P-gp相关的耐药性，又确定是否存在其他形式的耐药性。通过化学生物学方法，我们创建了25种柔红霉素衍生物，其糖结构发生了不同的变化。我们表明，通过这些更改，DNR的活动可以或多或少地有效。分子对接显示，将氨基改变为叠氮基或将单糖转化为二糖会使与P-gp的结合变差。进一步的对接研究表明，糖基的改变可将DNR的特异性从拓扑异构酶2毒改变为拓扑异构酶1毒。另外，糖修饰会在DNA螯合过程中改变化合物的特异性，从而导致microRNA水平的改变。这些研究的结合使我们对蒽环类药物的糖部分的关键元素有了更好的了解，并为我们设计更有效的抗癌药物提供了起点。从使用化学生物学方法创建的25种衍生物中，我们鉴定了两个新的蒽环类类似物（ADNR，ADNR3），它们避免了P-gp的结合并克服了P-gp介导的耐药性。为了研究独立于P-gp的白血病耐药性的其他新机制，使用了阿霉素，柔红霉素，ADNR和ADNR3来诱导新型的耐药性，这与microRNA调控有关。 microRNA微阵列分析表明，阿霉素（柔红霉素），柔红霉素（daunorubicin）在药物诱导的耐药性白血病细胞中，有5至15个microRNA上调至少1.5倍，而2至122个microRNA下调2至4852倍。 DNR），ADNR和ADNR3。在所有四个药物诱导的耐药细胞中，miR-221和miR-222始终下调2至15倍。这些耐药细胞中低水平的miR-221和miR-222会上调Kit蛋白（细胞存活的受体酪氨酸激酶）的4到8倍表达。在四个耐药细胞中转染miR-221和miR-222可恢复药物敏感性。这表明miR-221和miR-222的下调以及Kit的后续上调为白血病的耐药性提供了新的机制。 microRNA的应用可能为对抗白血病化学疗法的耐药性提供一种新颖的工具。通过实时RT-PCR，我们还确定在抗阿霉素和柔红霉素的K562白血病细胞中，miR-26a下调了1.49至3.60倍。阿霉素和柔红霉素抗性细胞中这些低水平的miR-26a上调cdk6的表达3.65和4.42倍。通过将miR-26a转染到耐药细胞（其中敲除了cdk6表达水平并恢复了药物敏感性），证实了miR-26a / cdk6调控机制。阿霉素的IC50值降低了11.01倍，柔红霉素的IC50值降低了12.97倍。这表明miR-26a的下调和cdk6的上调为耐药性提供了新的机制。 miR-26a对cdk6的调控为进一步研究microRNA对细胞周期蛋白的调控打开了大门。这样可以更好地了解microRNA在耐药中的作用，并允许将microRNA用作帮助对抗白血病中耐药性的工具。蒽环类药物治疗还上调了microRNA，包括miR-21，后者在四种耐药细胞系中上调了2.51到6.51倍。 miR-21由于其对肿瘤抑制物PTEN的调控而具有重要意义。这次暴动

著录项

  • 作者

    Gibbs, Seth.;

  • 作者单位

    The Ohio State University.;

  • 授予单位 The Ohio State University.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 212 p.
  • 总页数 212
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

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