Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center , El Paso, Texas 79905, United States.
J Nat Prod. 2013 Oct 25;76(10):1909-15. doi: 10.1021/np400441f. Epub 2013 Sep 30.
Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer. Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including prostate cancer are increasing. The present study focused on the cell cycle regulatory potential of the withanolide withaferin A (1) on prostate cancer cells. Compound 1 induced G2/M arrest in both prostate cancer cell lines (PC-3 and DU-145) when treated for 48 h. The G2/M arrest was accompanied by upregulation of phosphorylated Wee-1, phosphorylated histone H3, p21, and Aurora B. On the other hand, downregulation of cyclins (A2, B1, and E2) and a reduction in phosphorylated Cdc2 (Tyr15) were observed in 1-treated prostate cancer cells. In addition, decreased levels of phosphorylated Chk1 (Ser345) and Chk2 (Thr68) were evident in prostate cancer cells on treatment with 1. These results suggest that activation of Cdc2 leads to arrest in the M phase, with abnormal duplication, and initiation of mitotic catastrophe that results in cell death. In conclusion, these results show clearly the potential of 1 as a regulator of the G2/M phase of the cell cycle and as a therapeutic agent for prostate cancer.
细胞周期失调与前列腺癌的发病机制密切相关。针对包括前列腺癌在内的癌症，以 G0/G1 或 G2/M 期为靶点的细胞周期调节剂的临床试验正在增加。本研究集中于化合物 withaferin A（1）对前列腺癌细胞的细胞周期调控潜力。当用化合物 1 处理 48 小时时，它在两种前列腺癌细胞系（PC-3 和 DU-145）中诱导 G2/M 期阻滞。G2/M 期阻滞伴随着磷酸化 Wee-1、磷酸化组蛋白 H3、p21 和 Aurora B 的上调。另一方面，在用 1 处理的前列腺癌细胞中观察到细胞周期蛋白（A2、B1 和 E2）的下调和磷酸化 Cdc2（Tyr15）的减少。此外，在用 1 处理的前列腺癌细胞中，磷酸化 Chk1（Ser345）和 Chk2（Thr68）的水平明显降低。这些结果表明，Cdc2 的激活导致 M 期阻滞，出现异常复制，并启动有丝分裂灾难，导致细胞死亡。总之，这些结果清楚地表明 1 具有作为细胞周期 G2/M 期调节剂和作为前列腺癌治疗剂的潜力。
