Monastrol, a prototype anti-cancer drug that inhibits a mitotic kinesin, induces rapid bursts of axonal outgrowth from cultured postmitotic neurons
Monastrol, a prototype anti-cancer drug that inhibits a mitotic kinesin, induces rapid bursts of axonal outgrowth from cultured postmitotic neurons
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DOI：
10.1002/cm.10176
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发表时间：
2004-05-01
影响因子：
--
通讯作者：
Baas, PW
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文献类型：
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作者：
Haque, SA;Hasaka, TP;Baas, PW
终末有丝分裂后神经元继续表达许多已知在有丝分裂期间配置微管的驱动蛋白相关蛋白。抑制这些驱动蛋白的药物正被开发为抗癌剂，希望它们能抑制肿瘤细胞的增殖而不会对神经系统产生不利影响。被称为monastrol的原型抑制被称为Eg 5的驱动蛋白，该驱动蛋白对于维持半纺锤体的分离至关重要。Eg 5也在神经元中高度表达，特别是在发育期间。将培养的交感神经元暴露于monastrol几个小时，增加了轴突的数量和生长速度。随着时间的延长，轴突的总长度与对照组没有区别。感觉神经元表现出类似的轴突生长率的短期增加。然而，长时间暴露导致轴突变短，这表明感觉神经元可能对药物的毒性作用更敏感。尽管如此，这些培养物的整体健康状况仍然比用紫杉醇（一种常用于抗癌治疗的药物）治疗的培养物要稳健得多。在这些结果的基础上，我们得出结论，Eg 5通常产生的力量，反对轴突生长，大概是通过部分抑制微管的向前推进。我们推测，Eg 5的局部调节可能是一种手段，通过这种手段，神经元协调轴突生长的快速爆发与适当的环境线索。随着时间的推移，对神经元的相对温和的毒性作用对于有兴趣使用抗Eg 5药物进行癌症治疗的临床医生来说是一个充满希望的信号。细胞动力。Cytoskeleton 58：10-16，2004. (C)2004 Wiley-Liss，Inc.
Terminally postmitotic neurons continue to express many of the kinesin-related proteins known to configure microtubules during mitosis. Drugs that inhibit these kinesins are being developed as anti-cancer agents with the hope that they will inhibit proliferation of tumor cells without having adverse effects on the nervous system. The prototype, termed monastrol, inhibits the kinesin known as Eg5, which is essential for maintaining separation of the half-spindles. Eg5 is also highly expressed in neurons, particularly during development. Exposure of cultured sympathetic neurons to monastrol for a few hours increased both the number and the growth rate of the axons. With additional time, the overall lengths of the axons were indistinguishable from controls. Sensory neurons showed a similar short-term increase in axonal growth rate. However, prolonged exposure resulted in shorter axons, suggesting that sensory neurons may be more sensitive to toxic effects of the drug. Nevertheless, the overall health of the cultures was still far more robust than cultures treated with taxol, a drug commonly used for anti-cancer therapy. On the basis of these results, we conclude that Eg5 normally generates forces that oppose axonal growth, presumably by partially suppressing the forward advance of microtubules. We speculate that local regulation of Eg5 could be a means by which neurons coordinate rapid bursts of axonal growth with appropriate environmental cues. The comparatively modest toxic effects on the neurons over time are a hopeful sign for clinicians interested in using anti-Eg5 drugs for cancer therapy. Cell Motil. Cytoskeleton 58:10-16, 2004. (C) 2004 Wiley-Liss, Inc.