Miglietta Antonella, Bocca Claudia, Gabriel Ludovica
Department of Experimental Medicine and Oncology, University of Torino, Corso Raffaello 30, 10125 Torino, Italy.
Chem Biol Interact. 2002 Mar 20;139(3):283-99. doi: 10.1016/s0009-2797(02)00007-8.
We have compared the nature of interaction of certain taxanes with microtubular protein, and the mechanism of action underlying cytotoxic activity. Taxanes induced tubulin assembly in vitro, but only taxanes bearing side chain were capable of inducing the formation of stable tubulin polymers. Electron microscopy detections showed that taxane-induced polymers are structurally similar to microtubules formed by paclitaxel, with differences in length. Otherwise, light microscopy views have shown that intracellular microtubule network is deeply reorganized by taxanes into short fibers, unlike paclitaxel-bundled microtubules. Taxanes inhibited the growth of various human tumor cell lines, but cell cycle analysis did not always indicate a block in the G2/M phase. These agents alter some apoptotic signal transduction pathways, probably by a mechanism distinct from microtubule interaction. Briefly, the effectiveness of taxanes is closely related to their chemical structure, and depends on their interaction with microtubular protein. By virtue of this mechanism, some of these taxanes may provide usefulness for therapeutic improvements.
我们比较了某些紫杉烷类与微管蛋白的相互作用性质以及细胞毒性活性背后的作用机制。紫杉烷类在体外诱导微管蛋白组装，但只有带有侧链的紫杉烷类能够诱导稳定的微管蛋白聚合物形成。电子显微镜检测表明，紫杉烷类诱导的聚合物在结构上与紫杉醇形成的微管相似，只是长度不同。此外，光学显微镜观察表明，与紫杉醇束状微管不同，紫杉烷类可使细胞内微管网络深度重组为短纤维。紫杉烷类抑制多种人类肿瘤细胞系的生长，但细胞周期分析并不总是表明在G2/M期受阻。这些药物可能通过一种不同于微管相互作用的机制改变一些凋亡信号转导途径。简而言之，紫杉烷类的有效性与其化学结构密切相关，并取决于它们与微管蛋白的相互作用。凭借这一机制，其中一些紫杉烷类可能对治疗改善有用。
