Mechanisms of Taxol-induced cell death are concentration dependent.
Mechanisms of Taxol-induced cell death are concentration dependent.
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发表时间：
1998-08
期刊：
影响因子：
11.2
通讯作者：
K. Torres;S. B. Horwitz
中科院分区：
文献类型：
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作者：
K. Torres;S. B. Horwitz
虽然紫杉醇稳定细胞微管的能力被广泛接受，但紫杉醇诱导生长停滞和细胞死亡的机制仍不清楚。最近的证据表明，紫杉醇改变特定的细胞内信号转导事件，如Raf-1激酶的激活，这可能是药物诱导的细胞凋亡所必需的。为了确定Raf-1激酶激活是否发生在不同浓度的紫杉醇和响应于正常微管细胞骨架的破坏，A549细胞用不同浓度的紫杉醇处理，然后分析Raf-1激活和微管细胞骨架。Raf-1的活化在紫杉醇浓度为9 nM或更高时观察到。然而，在较低的紫杉醇浓度（1-7 nM）下观察到正常微管细胞骨架的破坏，表明该过程在Raf-1活化不存在的情况下开始。Raf-1激活与G2-M阻滞的诱导相关。Raf-1的缺失导致细胞聚集在细胞周期的G2-M期，表明Raf-1可能在有丝分裂的通道中起重要作用。支持这一观点的是Raf-1在有丝分裂细胞中被激活。低浓度的紫杉醇诱导细胞死亡的情况下，Raf-1的激活，表明紫杉醇诱导的细胞死亡不依赖于Raf-1的激活。当药物浓度低于Raf-1激活所需的临界浓度时，p53和p21（WAF-1）的诱导与Raf-1无关。这些研究表明，紫杉醇介导的细胞死亡可能由两种不同的机制引起。在低紫杉醇浓度（或= 9 nM）下，细胞死亡可能是由Raf-1依赖性途径导致的终末有丝分裂停滞的结果。
Although the ability of Taxol to stabilize cellular microtubules is well accepted, the mechanisms by which Taxol induces growth arrest and cell death remain unclear. Recent evidence indicates that Taxol alters specific intracellular signal transduction events, such as the activation of Raf-1 kinase, that may be essential for drug-induced apoptosis. To determine whether Raf-1 kinase activation occurs at different concentrations of Taxol and in response to disruption of the normal microtubule cytoskeleton, A549 cells were treated with different concentrations of Taxol after which Raf-1 activation and the microtubule cytoskeleton were analyzed. Raf-1 activation was observed at Taxol concentrations of 9 nM and greater. However, disruption of the normal microtubule cytoskeleton was seen at lower Taxol concentrations (1-7 nM), indicating that this process begins in the absence of Raf-1 activation. Raf-1 activation correlated with the induction of a G2-M block. Depletion of Raf-1 resulted in the accumulation of cells in the G2-M phase of the cell cycle, suggesting that Raf-1 may play an important role in the passage through mitosis. Supporting this idea, Raf-1 was activated in mitotic cells. Low concentrations of Taxol induced cell death in the absence of Raf-1 activation, indicating that Taxol-induced cell death is not dependent on Raf-1 activation. At concentrations of drug lower than the critical concentration required for Raf-1 activation, p53 and p21(WAF-1) were induced independently of Raf-1. These studies suggest that Taxol-mediated cell death may result from two different mechanisms. At low Taxol concentrations ( or = 9 nM) cell death may be the result of a terminal mitotic arrest occurring by a Raf-1-dependent pathway.