文章：

关于维他菲林-A抗癌活性的分子机制研究：抑制生存素信号通路

Molecular Insights into the Anticancer Activity of Withaferin-A: The Inhibition of Survivin Signaling

原文发布日期：5 September 2024

DOI: 10.3390/cancers16173090

类型: Article

开放获取: 是

英文摘要：

Survivin, a member of the IAP family, functions as a homodimer and inhibits caspases, the key enzymes involved in apoptosis. Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Due to the high cost and adverse side effects of synthetic drugs, natural compounds with similar activity have also been in demand. In this study, we conducted molecular docking assays to evaluate the ability of Wi-A and Wi-N to block Survivin dimerization. We found that Wi-A, but not Wi-N, can bind to and prevent the homodimerization of Survivin, similar to YM-155. Therefore, we prepared a Wi-A-rich extract from Ashwagandha leaves (Wi-AREAL). Experimental analyses of human cervical carcinoma cells (HeLa and ME-180) treated with Wi-AREAL (0.05–0.1%) included assessments of viability, apoptosis, cell cycle, migration, invasion, and the expression levels (mRNA and protein) of molecular markers associated with these phenotypes. We found that Wi-AREAL led to growth arrest mediated by the upregulation of p21WAF1and the downregulation of several proteins (CDK1, Cyclin B, pRb) involved in cell cycle progression. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial–mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment.

摘要翻译： 

存活素（Survivin）作为凋亡抑制蛋白家族成员，以同源二聚体形式发挥功能，能够抑制细胞凋亡关键酶——半胱天冬酶。目前已有多种存活素抑制剂（如YM-155、Debio1143、EM1421、LQZ-7I和TL32711）作为潜在抗癌药物进入临床试验验证阶段。鉴于合成药物成本高昂且存在不良反应，具有相似活性的天然化合物备受关注。本研究通过分子对接实验评估了Wi-A与Wi-N阻断存活素二聚化的能力，发现Wi-A（而非Wi-N）能够像YM-155一样结合并抑制存活素的同源二聚化。为此，我们从睡茄叶片中制备了富含Wi-A的提取物（Wi-AREAL）。通过对Wi-AREAL（0.05–0.1%）处理的人宫颈癌细胞（HeLa和ME-180）进行实验分析，包括细胞活力、凋亡、周期、迁移侵袭能力检测，以及相关表型分子标志物（mRNA与蛋白）表达水平评估。研究发现：Wi-AREAL通过上调p21WAF1、下调细胞周期相关蛋白（CDK1、Cyclin B、pRb）介导生长阻滞；同时通过降低PARP-1和Bcl-2水平、增加procaspase-3表达、提升细胞色素C含量激活凋亡信号通路。此外，使用无毒低浓度（0.01%）Wi-AREAL处理细胞可抑制迁移侵袭能力及上皮-间质转化信号传导。通过计算与实验相结合的方法，本研究揭示了Wi-A与Wi-AREAL作为天然存活素抑制剂的潜力，为癌症治疗提供了新思路。

原文链接：

Molecular Insights into the Anticancer Activity of Withaferin-A: The Inhibition of Survivin Signaling