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首页> 外文学位 >Mechanism of action of coumarin natural products that inhibit cell proliferation and potentiate the anticancer drug taxol.
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Mechanism of action of coumarin natural products that inhibit cell proliferation and potentiate the anticancer drug taxol.

机译：香豆素天然产物抑制细胞增殖并增强抗癌药物紫杉醇的作用机理。

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摘要

Investigations of ancient botanical medicinal formulations have proven to provide a rich source of drugs with therapeutic merit. An analysis of medicinal plant formulations used by traditional healers of ancient Persia to induce abortions is reported here. By investigating the medical and pharmacological literature on the medicinal properties of the plant species used, I found that many of the plant species demonstrate antineoplastic or cytotoxic activities and are rich in coumarin compounds. In studies on the anti-proliferative actions of coumarin compounds, dicoumarol (a coumarin anticoagulant) inhibited the first cleavage of sea urchin embryos in a concentration dependent manner with 50% inhibition occurring at a concentration of 10 μM. Because first cleavage in sea urchin embryos is highly selective for microtubule-targeted agents, I thought the active compounds might inhibit cell division by interacting with tubulin or microtubules. I found that dicoumarol binds to bovine brain tubulin with a Kd of 22 μM, and that 0.1 μM dicoumarol strongly stabilizes the growing and shortening dynamics at the plus ends of the microtubules in vitro. Dicoumarol reduced the rate and extent of shortening, it increased the percentage of time the microtubules spent in an attenuated (paused) state, and it reduced the overall dynamicity of the microtubulet. The anti-mitotic effects of the widely used cancer chemotherapeutic agent taxol (paclitaxel) are also mediated by suppressing microtubule dynamics. Indirect immunofluorescence microscopic imaging of microtubules and 4,6-diamidino-2-phenylindole imaging of in cell chromatin characterized the effects of the drugs on the organization of microtubules and chromosomes in metaphase spindles. Dicoumarol produced abnormal organization of mitotic spindle microtubules with chromosomes that had not congressed to the metaphase plate. In addition, exposure to combinations of taxol and dicoumarol potentiated the inhibition of cell division of sea urchin embryos. The results suggest that the anti-proliferative mechanism of action of dicoumarol and possibly related pharmacophores are mediated by tubulin binding and the stabilization of spindle microtubule dynamics. Because of its low toxicity and simple chemical structure, there is potential interest to explore combinations of anti-mitotic coumarins with other chemotherapeutic agents to improve efficacy and lower toxicity.
机译：事实证明，对古老的植物药配方的研究可提供具有治疗价值的丰富药物来源。此处报告了对古代波斯传统治疗师用于引产的药用植物配方的分析。通过研究有关所用植物物种的医学特性的医学和药理文献，我发现许多植物物种均表现出抗肿瘤或细胞毒性活性，并且富含香豆素化合物。在有关香豆素化合物的抗增殖作用的研究中，双香豆酚（一种香豆素抗凝剂）以浓度依赖的方式抑制了海胆胚胎的首次裂解，在10μM的浓度下发生了50％的抑制作用。由于海胆胚胎中的首次裂解对微管靶向药物具有高度选择性，因此我认为活性化合物可能通过与微管蛋白或微管相互作用来抑制细胞分裂。我发现地高富乐与牛脑微管蛋白结合，其K d 为22μM，而0.1μM地高富乐在体外微管正末端强烈稳定了生长和缩短动力，斜体>。地香豆酚降低了缩短的速率和程度，增加了微管在减毒（暂停）状态下花费的时间百分比，并降低了微管的整体动态性。广泛使用的癌症化疗剂紫杉醇（紫杉醇）的抗有丝分裂作用也通过抑制微管动力学来介导。细胞内染色质的微管间接免疫荧光显微成像和4,6-二mid基-2-苯基吲哚成像表征了药物对中期纺锤体中微管和染色体组织的影响。 Dicoumarol产生有丝分裂纺锤体微管的异常组织，其染色体未与中期板融合。另外，暴露于紫杉醇和双香豆酚的组合可增强对海胆胚胎细胞分裂的抑制作用。结果表明，双香豆酚和可能的相关药效团的抗增殖作用机制是由微管蛋白结合和纺锤体微管动力学的稳定介导的。由于它的低毒性和简单的化学结构，因此有兴趣研究抗有丝分裂香豆素与其他化学治疗剂的组合以提高疗效和降低毒性。

著录项

  • 作者

    Madari, Hamta.;

  • 作者单位

    University of California, Santa Barbara.;

  • 授予单位 University of California, Santa Barbara.;
  • 学科 Biology Molecular.; Health Sciences Oncology.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 180 p.
  • 总页数 180
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;肿瘤学;药理学;
  • 关键词

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