Mitotic catastrophe and apoptosis induced by Docetaxel in hormone-refractory prostate cancer cells
Mitotic catastrophe and apoptosis induced by Docetaxel in hormone-refractory prostate cancer cells
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DOI：
10.1002/jcp.21522
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发表时间：
2008-11-01
影响因子：
5.6
通讯作者：
Silvestrini, Rosella
中科院分区：
文献类型：
--
作者：
Fabbri, Francesco;Amadori, Dino;Silvestrini, Rosella
在不同的实验和临床环境下进行的研究表明，多西紫杉醇(Doc)对多种肿瘤有效，并通过多种作用机制发挥其活性。然而，Doc诱导的导致细胞死亡的一系列事件仍不完全清楚。此外，Doc是如何诱导有丝分裂灾难的，以及这一过程是在最终事件中还是随后发生了细胞凋亡或坏死，目前还不完全清楚。我们通过分析细胞周期扰动，研究了Doc在激素非依赖性前列腺癌细胞中触发细胞死亡的机制。凋亡相关标记物的表达和细胞形态的改变。DOC诱导G2/M期一过性增加，随后出现G0/1亚二倍体和超二倍体细胞，p21表达增强。高达70%的细胞发生时间和浓度依赖性的细胞凋亡，伴随着bcl2的磷酸化，随后caspase-2和caspase-3被激活。综上所述，DOC似乎通过两种形式的有丝分裂退出，通过有丝分裂突变，同时伴随着p21表达的增加和caspase-2的激活，来启动激素非依赖性前列腺癌细胞的凋亡。
Studies performed in different experimental and clinical settings have shown that Docetaxel (Doc) is effective in a wide range of tumors and that it exerts its activity through multiple mechanisms of action. However, the sequence of events induced by Doc which leads to cell death is still not fully understood. Moreover, it is not completely clear how Doc induces mitotic catastrophe and whether this process is in end event or followed by apoptosis or necrosis. We investigated the mechanisms by which Doc triggers cell death in hormone-refractory prostate cancer cells by analyzing cell cycle perturbations. apoptosis-related marker expression, and morphologic cell alterations. Doc induced a transient increase in G2/M phase followed by the appearance of G0/1 hypo- and hyperdiploid cells and increased p21 expression. Time- and concentration-dependent apoptosis was induced in up to 70% of cells, in concomitance with Bcl-2 phosphorylation, which was followed by caspase-2 and -3 activation. In conclusion, Doc would seem to trigger apoptosis in hormone-refractory prostate cancer cells via mitotic catastrophe through two forms of mitotic exit, in concomitance with increased p21 expression and caspase-2 activation.