Pisano C, Battistoni A, Antoccia A, Degrassi F, Tanzarella C
Research and Development, Sigma-Tau, Pomezia, Rome, Department of Genetics and Molecular Biology, University 'La Sapienza', Rome, Italy.
Mutagenesis. 2000 Nov;15(6):507-15. doi: 10.1093/mutage/15.6.507.
Many aneugenic compounds are known to affect one or several components of the mitotic apparatus. The mechanisms and targets of the aneuploidy-inducing activity of the benzimidazole derivative thiabendazole remain uninvestigated. In our experiments we found that thiabendazole-treated Chinese hamster cells (Cl-1) exhibited low levels of newly synthesized tubulin, indicating microtubule poisoning. In addition, microtubule growth and organization were substantially affected at mitosis. This was revealed by the reduced length of both interpolar and astral microtubules. Furthermore, thiabendazole strongly induced multipolar and asymmetric alpha-tubulin-positive metaphase spindles, characterized, however, by the absence of fragmentation of centrosome material as evaluated by anti-gamma-tubulin antibody staining. Interestingly, we found that microtubule poisoning induced by thiabendazole was qualitatively different from that of colchicine, the best known microtubule depolymerizing agent. In fact, in interphase cells colchicine was comparatively more effective than thiabendazole in promoting depolymerization of cytoplasmic microtubules. However, colchicine could not depolymerize a sub-population of stable, acetylated microtubules, which were however significantly reduced after thiabendazole exposure. In conclusion, the capability of thiabendazole to promote chromosomal malsegregation could be related to an effect on microtubule polymerization that specifically promotes formation of aberrant spindles.
已知许多非整倍体诱导化合物会影响有丝分裂装置的一个或多个组件。苯并咪唑衍生物噻苯达唑诱导非整倍体活性的机制和靶点仍未得到研究。在我们的实验中，我们发现用噻苯达唑处理的中国仓鼠细胞（Cl-1）新合成的微管蛋白水平较低，表明存在微管中毒现象。此外，在有丝分裂时微管的生长和组织受到了显著影响。这通过极间微管和星体微管长度的缩短得以体现。此外，噻苯达唑强烈诱导多极和不对称的α-微管蛋白阳性中期纺锤体，然而，通过抗γ-微管蛋白抗体染色评估，其特征是中心体物质没有碎片化。有趣的是，我们发现噻苯达唑诱导的微管中毒在性质上与秋水仙碱不同，秋水仙碱是最著名的微管解聚剂。事实上，在间期细胞中，秋水仙碱在促进细胞质微管解聚方面比噻苯达唑相对更有效。然而，秋水仙碱不能使一部分稳定的、乙酰化的微管解聚，不过在噻苯达唑处理后这些微管显著减少。总之，噻苯达唑促进染色体错分的能力可能与对微管聚合的影响有关，这种影响特别促进异常纺锤体的形成。
