Fabbri Francesco, Amadori Dino, Carloni Silvia, Brigliadori Giovanni, Tesei Anna, Ulivi Paola, Rosetti Marco, Vannini Ivan, Arienti Chiara, Zoli Wainer, Silvestrini Rosella
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola (FC), Italy.
J Cell Physiol. 2008 Nov;217(2):494-501. doi: 10.1002/jcp.21522.
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 an 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.
在不同实验和临床环境中进行的研究表明，多西他赛（Doc）对多种肿瘤有效，且通过多种作用机制发挥其活性。然而，Doc诱导导致细胞死亡的一系列事件仍未完全明了。此外，Doc如何诱导有丝分裂灾难以及该过程是终末事件还是继之以凋亡或坏死也不完全清楚。我们通过分析细胞周期扰动、凋亡相关标志物表达及细胞形态改变，研究了Doc在激素难治性前列腺癌细胞中触发细胞死亡的机制。Doc诱导G2/M期短暂增加，随后出现G0/1亚二倍体和超二倍体细胞，并增加p21表达。高达70%的细胞诱导出时间和浓度依赖性凋亡，同时伴有Bcl-2磷酸化，随后是caspase-2和-3激活。总之，Doc似乎通过有丝分裂灾难，经由两种有丝分裂退出形式，在激素难治性前列腺癌细胞中触发凋亡，同时伴有p21表达增加和caspase-2激活。
