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抗有丝分裂抗真菌化合物苯菌灵通过与微管蛋白中的一个新位点结合,抑制脑微管聚合、动力学以及有丝分裂时的癌细胞增殖。

Antimitotic antifungal compound benomyl inhibits brain microtubule polymerization and dynamics and cancer cell proliferation at mitosis, by binding to a novel site in tubulin.

作者信息

Gupta Kamlesh, Bishop Jamie, Peck Austin, Brown Julie, Wilson Leslie, Panda Dulal

机构信息

School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Mumbai India 400076.

出版信息

Biochemistry. 2004 Jun 1;43(21):6645-55. doi: 10.1021/bi036112v.

Abstract

The antifungal agent benomyl [methyl-1-(butylcarbamoyl)-2-benzimidazolecarbamate] is used throughout the world against a wide range of agricultural fungal diseases. In this paper, we investigated the interaction of benomyl with mammalian brain tubulin and microtubules. Using the hydrophobic fluorescent probe 1-anilinonaphthalene-8-sulfonic acid, benomyl was found to bind to brain tubulin with a dissociation constant of 11.9 +/- 1.2 microM. Further, benomyl bound to at a novel site, distinct from the well-characterized colchicine and vinblastine binding sites. Benomyl altered the far-UV circular dichroism spectrum of tubulin and reduced the accessibility of its cysteine residues to modification by 5,5'-dithiobis-2-nitrobenzoic acid, indicating that benomyl binding to tubulin induces a conformational change in the tubulin. Benomyl inhibited the polymerization of brain tubulin into microtubules, with 50% inhibition occurring at a concentration of 70-75 microM. Furthermore, it strongly suppressed the dynamic instability behavior of individual brain microtubules in vitro as determined by video microscopy. It reduced the growing and shortening rates of the microtubules but did not alter the catastrophe or rescue frequencies. The unexpected potency of benomyl against mammalian microtubule polymerization and dynamics prompted us to investigate the effects of benomyl on HeLa cell proliferation and mitosis. Benomyl inhibited proliferation of the cells with an IC(50) of 5 microM, and it blocked mitotic spindle function by perturbing microtubule and chromosome organization. The greater than expected actions of benomyl on mammalian microtubules and mitosis together with its relatively low toxicity suggest that it might be useful as an adjuvant in cancer chemotherapy.

摘要

抗真菌剂苯菌灵[甲基-1-(丁基氨基甲酰基)-2-苯并咪唑氨基甲酸酯]在全球范围内用于防治多种农业真菌病害。在本文中,我们研究了苯菌灵与哺乳动物脑微管蛋白和微管的相互作用。使用疏水荧光探针1-苯胺基萘-8-磺酸,发现苯菌灵与脑微管蛋白结合,解离常数为11.9±1.2微摩尔。此外,苯菌灵结合在一个新位点,不同于已充分表征的秋水仙碱和长春花碱结合位点。苯菌灵改变了微管蛋白的远紫外圆二色光谱,并降低了其半胱氨酸残基被5,5'-二硫代双-2-硝基苯甲酸修饰的可及性,表明苯菌灵与微管蛋白的结合诱导了微管蛋白的构象变化。苯菌灵抑制脑微管蛋白聚合成微管,在浓度为70-75微摩尔时出现50%的抑制。此外,通过视频显微镜测定,它在体外强烈抑制单个脑微管的动态不稳定性行为。它降低了微管的生长和缩短速率,但没有改变灾难或救援频率。苯菌灵对哺乳动物微管聚合和动力学的意外效力促使我们研究苯菌灵对HeLa细胞增殖和有丝分裂的影响。苯菌灵以5微摩尔的IC(50)抑制细胞增殖,并通过扰乱微管和染色体组织来阻断有丝分裂纺锤体功能。苯菌灵对哺乳动物微管和有丝分裂的作用大于预期,且其毒性相对较低,这表明它可能作为癌症化疗的佐剂有用。

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