Ayurvedic Medicine Constituent Withaferin A Causes G2 and M Phase Cell Cycle Arrest in Human Breast Cancer Cells
Ayurvedic Medicine Constituent Withaferin A Causes G2 and M Phase Cell Cycle Arrest in Human Breast Cancer Cells
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DOI：
10.1080/01635580802381477
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发表时间：
2008-01-01
影响因子：
2.9
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
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作者：
Stan, Silvia D.;Zeng, Yan;Singh, Shivendra V.
Withaferin A（WA）来自药用植物Withania somnifera，几个世纪以来一直安全地用于印度阿育吠陀医学，用于治疗各种疾病。我们现在证明WA治疗导致人乳腺癌细胞G2期和有丝分裂阻滞。用WA处理MDA-MB-231（雌激素非依赖性）和MCF-7（雌激素响应性）细胞系导致G2-M分数的浓度和时间依赖性增加，这与细胞周期蛋白依赖性激酶1（CdkI）、细胞分裂周期25 C（Cdc 25 C）和/或Cdc 25 B蛋白水平的降低相关，导致酪氨酸15磷酸化（无活性）CdkI的积累。Cdc 25 C的异位表达对WA介导的MDA-MB-231细胞G2-M期细胞周期阻滞具有部分但显著的保护作用。通过荧光显微镜和Ser 10磷酸化组蛋白H3分析判断，WA处理的MDA-MB-231和MCF-7细胞也被阻滞在有丝分裂中。有丝分裂阻滞导致暴露于WA伴随着后期促进复合物/细胞核小体底物securin的蛋白质水平的增加。因此，G2-M期阻滞可能是WA抗人乳腺癌细胞增殖的重要机制。
Withaferin A (WA) is derived from the medicinal plant Withania somnifera that has been safely used for centuries in the Indian Ayurvedic medicine for treatment of various ailments. We now demonstrate that WA treatment causes G2 and mitotic arrest in human breast cancer cells. Treatment of MDA-MB-231 (estrogen-independent) and MCF-7 (estrogen-responsive) cell lines with WA resulted in a concentration- and time-dependent increase in G2-M fraction, which correlated with a decrease in levels of cyclin-dependent kinase 1 (CdkI), cell division cycle 25C (Cdc25C) and/or Cdc25B proteins, leading to accumulation of Tyrosine15 phosphorylated (inactive) CdkI. Ectopic expression of Cdc25C conferred partial yet significant protection against WA-mediated G2-M phase cell cycle arrest in MDA-MB-231 cells. The WA-treated MDA-MB-231 and MCF-7 cells were also arrested in mitosis as judged by fluorescence microscopy and analysis of Ser10 phosphorylated histone H3. Mitotic arrest resulting from exposure to WA was accompanied by an increase in the protein level of anaphase promoting complex/cyclosome substrate securin. In conclusion, the results of this study suggest that G2-M phase cell cycle arrest may be an important mechanism in antiproliferative effect of WA against human breast cancer cells.