Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
Cell Cycle. 2011 Jul 1;10(13):2162-71. doi: 10.4161/cc.10.13.16238.
Taccalonolide A is a microtubule stabilizer that has cellular effects almost identical to paclitaxel. However, biochemical studies show that, unlike paclitaxel, taccalonolide A does not enhance purified tubulin polymerization or bind tubulin/microtubules. Mechanistic studies aimed at understanding the nature of the differences between taccalonolide A and paclitaxel were conducted. Our results show that taccalonolide A causes bundling of interphase microtubules at concentrations that cause antiproliferative effects. In contrast, the concentration of paclitaxel that initiates microtubule bundling is 31-fold higher than its IC 50. Taccalonolide A's effects are further differentiated from paclitaxel in that it is unable to enhance the polymerization of tubulin in cellular extracts. This finding extends previous biochemical results with purified brain tubulin to demonstrate that taccalonolide A requires more than tubulin and a full complement of cytosolic proteins to cause microtubule stabilization. Reversibility studies were conducted and show that the cellular effects of taccalonolide A persist after drug washout. In contrast, other microtubule stabilizers, including paclitaxel and laulimalide, demonstrate a much higher degree of cellular reversibility in both short-term proliferation and long-term clonogenic assays. The propensity of taccalonolide A to alter interphase microtubules at antiproliferative concentrations as well as its high degree of cellular persistence may explain why taccalonolide A is more potent in vivo than would be expected from cellular studies. The close linkage between the microtubule bundling and antiproliferative effects of taccalonolide A is of interest given the recent hypothesis that the effects of microtubule targeting agents on interphase microtubules might play a prominent role in their clinical anticancer efficacy.
Taccalonolide A 是一种微管稳定剂，其细胞效应几乎与紫杉醇完全相同。然而，生化研究表明，与紫杉醇不同，Taccalonolide A 不会增强纯化的微管蛋白聚合或结合微管/微管。为了了解 Taccalonolide A 和紫杉醇之间差异的性质，进行了机制研究。我们的结果表明，Taccalonolide A 在引起抗增殖作用的浓度下引起间期微管的束状。相比之下，引发微管束状的紫杉醇浓度比其 IC 50 高 31 倍。Taccalonolide A 的作用进一步与紫杉醇区分开来，因为它无法增强细胞提取物中微管蛋白的聚合。这一发现扩展了以前用纯化的脑微管进行的生化结果，表明 Taccalonolide A 需要微管和完整的胞质蛋白补充才能引起微管稳定。进行了逆转研究，结果表明 Taccalonolide A 的细胞作用在药物冲洗后仍然存在。相比之下，其他微管稳定剂，包括紫杉醇和 laumalide，在短期增殖和长期集落形成测定中表现出更高程度的细胞逆转性。Taccalonolide A 在抗增殖浓度下改变间期微管的倾向以及其高细胞持久性可能解释了为什么 Taccalonolide A 在体内比细胞研究预期的更有效。鉴于最近的假设，即微管靶向剂对间期微管的作用可能在其临床抗癌疗效中发挥重要作用，Taccalonolide A 的微管束状和抗增殖作用之间的紧密联系很有趣。
