Foss Margit, Wilcox Buck W L, Alsop G Bradley, Zhang Dahong
Department of Zoology, Oregon State University, Corvallis, Oregon, USA.
PLoS One. 2008 Jan 23;3(1):e1476. doi: 10.1371/journal.pone.0001476.
Taxol is a potent anti-mitotic drug used in chemotherapy, angioplastic stents, and cell biology research. By binding and stabilizing microtubules, Taxol inhibits their dynamics, crucial for cell division, motility, and survival. The drug has also been reported to induce formation of asters and bundles composed of stabilized microtubules. Surprisingly, at commonly used concentrations, Taxol forms crystals that rapidly bind fluorescent tubulin subunits, generating structures with an uncanny resemblance to microtubule asters and bundles. Kinetic and topological considerations suggest that tubulin subunits, rather than microtubules, bind the crystals. This sequestration of tubulin from the subunit pool would be expected to shift the equilibrium of free to polymerized tubulin to disfavor assembly. Our results imply that some previously reported Taxol-induced asters or bundles could include or be composed of tubulin-decorated Taxol crystals. Thus, reevaluation of certain morphological, chemical, and physical properties of Taxol-treated microtubules may be necessary. Moreover, our findings suggest a novel mechanism for chemotherapy-induced cytotoxicity in non-dividing cells, with far-reaching medical implications.
紫杉醇是一种强效抗有丝分裂药物，用于化疗、血管成形支架和细胞生物学研究。通过结合并稳定微管，紫杉醇抑制其动态变化，而微管动态变化对细胞分裂、运动和存活至关重要。据报道，该药物还能诱导由稳定微管组成的星体和束状结构形成。令人惊讶的是，在常用浓度下，紫杉醇会形成晶体，这些晶体能迅速结合荧光微管蛋白亚基，生成与微管星体和束状结构极为相似的结构。动力学和拓扑学考量表明，是微管蛋白亚基而非微管与晶体结合。这种从亚基库中隔离微管蛋白的情况预计会使游离微管蛋白与聚合微管蛋白的平衡向不利于组装的方向转变。我们的结果表明，一些先前报道的紫杉醇诱导的星体或束状结构可能包含或由微管蛋白修饰的紫杉醇晶体组成。因此，可能有必要重新评估紫杉醇处理过的微管的某些形态、化学和物理性质。此外，我们的发现提示了一种非分裂细胞中化疗诱导细胞毒性的新机制，具有深远的医学意义。
