Roscovitine Differentially Affects Asynchronously Growing and Synchronized Human MCF-7 Breast Cancer Cells
Roscovitine Differentially Affects Asynchronously Growing and Synchronized Human MCF-7 Breast Cancer Cells
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DOI：
10.1111/j.1749-6632.2009.04717.x
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Wesierska-Gadek, Jozefa
中科院分区：
文献类型：
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作者：
Maurer, Margarita;Komina, Oxana;Wesierska-Gadek, Jozefa
Roscovitine（ROSC）是一种细胞周期蛋白依赖性激酶（CDKs）的选择性阻断剂，通过诱导细胞周期阻滞和p53介导的凋亡，有效抑制指数生长的人MCF-7乳腺癌细胞的增殖。ROSC以时间和浓度依赖性方式将MCF-7细胞阻滞在G（2）期。然而，ROSC对人二倍体成纤维细胞发挥弱得多的抗增殖作用。因此，在这项研究中，我们质疑ROSC的抗增殖作用是否以及在多大程度上取决于暴露于药物的癌细胞的细胞周期状态。我们研究了ROSC对异步的、指数生长的和同步的人MCF-7乳腺癌细胞的作用。去血清后MCF-7细胞阻滞于G（1）期，而羟基脲则阻滞于S期。血清再灌流后，同步化细胞在12 h后开始重新进入活跃的细胞周期。G1期同步化细胞暴露于ROSC延长了细胞周期停滞，24 h后S期细胞减少。ROSC给药后，细胞从G（1）阻滞中释放4小时，出现类似但较弱的趋势。ROSC减少S期细胞的频率。将从G（1）停滞释放的MCF-7细胞暴露于ROSC 24小时，导致G（1）细胞群增加20%。将S期阻滞解除的MCF-7细胞暴露于ROSC中，S期细胞的比例增加。这些结果表明，治疗开始前癌细胞的细胞周期状态决定了治疗的结果。
Roscovitine (ROSC), a selective blocker of cyclin-dependent kinases (CDKs) efficiently inhibits proliferation of exponentially growing human MCF-7 breast cancer cells by induction of cell cycle arrest and p53-mediated apoptosis. ROSC blocks MCF-7 cells in G(2) phase in a time- and concentration-dependent manner. However, ROSC exerts a much weaker antiproliferative effect on human diploid fibroblasts. Therefore, in this study we questioned whether and to what extent the antiproliferative effect of ROSC depends on the cell cycle status of cancer cells exposed to the drug. We investigated the action of ROSC on asynchronous, exponentially growing, and on synchronized human MCF-7 breast cancer cells. MCF-7 cells were arrested in G(1) phase after serum withdrawal and in S phase by hydroxyurea. After serum refeeding, synchronized cells started to reenter the active cell cycle after 12 h. Exposure of G(1)-synchronized cells to ROSC prolonged the cell cycle arrest and was accompanied by a decrease in S-phase cells after 24 h. A similar but weaker trend occurred after ROSC administration, to cells released from G(1) arrest for 4 h. ROSC diminished the frequency of S-phase cells. Exposure of MCF-7 cells released from G(1) arrest to ROSC for 24 h resulted in an increase of the G(1)-cell population by 20%. Exposure to ROSC of MCF-7 cells released from S-phase block increased the ratio of S-phase cells. These results indicate that the cell cycle status of cancer cells prior to the onset of therapy determines the outcome of treatment.