Molecular profling of docetaxel cytotoxicity in breast cancer cells:: uncoupling of aberrant mitosis and apoptosis
Molecular profling of docetaxel cytotoxicity in breast cancer cells:: uncoupling of aberrant mitosis and apoptosis
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DOI：
10.1038/sj.onc.1210102
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发表时间：
2007-05-03
期刊：
影响因子：
8
通讯作者：
Moreno-Bueno, G.
中科院分区：
文献类型：
--
作者：
Hernandez-Vargas, H.;Palacios, J.;Moreno-Bueno, G.
在微管靶向药物中，多西紫杉醇因其良好的治疗指数而受到关注。临床试验强调了其治疗晚期乳腺癌的潜力，尽管在这种情况下对其分子作用模式知之甚少。我们描述了多西紫杉醇在两种著名的人乳腺癌细胞系中引起的分子变化。通过双相敏感性曲线提出了两种药物浓度不同的作用机制，并通过细胞形态、细胞周期和细胞死亡变化进一步验证了其作用机制。2 ~ 4纳摩尔多西紫杉醇诱导有丝分裂异常，随后出现晚期坏死，100纳摩尔多西紫杉醇诱导有丝分裂停止，随后发生细胞凋亡。通过同步细胞的功能研究以及多西他赛与蛋白酶体抑制剂MG132的联合研究表明，有丝分裂期是发生次二倍体的必要条件。转录。不同细胞系和多西紫杉醇浓度的Ling表现出差异，两种细胞系的细胞周期、细胞死亡和结构基因共同调控。虽然p53靶点主要是在MCF7细胞中用低浓度药物诱导的，但通过使用等基因shp53细胞系排除了其在多西紫杉醇细胞毒性双重机制中的相关性。本研究中显示的许多基因可能参与了多西紫杉醇在不同浓度下抑制乳腺癌细胞生长的双重机制。这些发现为合理加强多西紫杉醇的治疗，考虑较低的浓度和较好的联合用药提供了依据。
Among microtubule-targeting agents, docetaxel has received recent interest owing to its good therapeutic index. Clinical trials have underlined its potential for the treatment of advanced breast cancer, although little is known about its molecular mode of action in this context. We characterized the molecular changes induced by docetaxel in two well-known human breast carcinoma cell lines. Two mechanisms of action according to drug concentration were suggested by a biphasic sensitivity curve, and were further validated by cell morphology, cell cycle and cell death changes. Two to four nanomolar docetaxel induced aberrant mitosis followed by late necrosis, and 100 nM docetaxel induced mitotic arrest followed by apoptosis. Passing through mitosis phase was a requirement for hypodiploidy to occur, as shown by functional studies in synchronized cells and by combining docetaxel with the proteasome inhibitor MG132. Transcriptional pro. ling showed differences according to cell line and docetaxel concentration, with cell cycle, cell death and structural genes commonly regulated in both cell lines. Although p53 targets were mainly induced with low concentration of drug in MCF7 cells, its relevance in the dual mechanism of docetaxel cytotoxicity was ruled out by using an isogenic shp53 cell line. Many of the genes shown in this study may contribute to the dual mechanism by which docetaxel inhibits the growth of breast cancer cells at different concentrations. These findings provide a basis for rationally enhancing docetaxel therapy, considering lower concentrations, and better drug combinations.