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 p21WAF1 and 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.

中文翻译：

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醉茄素 A 抗癌活性的分子洞察：生存素信号传导的抑制。


Survivin 是 IAP 家族的成员，作为同二聚体发挥作用并抑制半胱天冬酶（参与细胞凋亡的关键酶）。几种 Survivin 抑制剂，包括 YM-155、Debio1143、EM1421、LQZ-7I 和 TL32711，已成为等待临床试验验证的潜在抗癌药物。由于合成药物成本高且副作用大，因此也需要具有类似活性的天然化合物。在本研究中，我们进行了分子对接测定，以评估 Wi-A 和 Wi-N 阻断 Survivin 二聚化的能力。我们发现 Wi-A（而非 Wi-N）可以结合并阻止 Survivin 的同二聚化，类似于 YM-155。因此，我们从 Ashwagandha 叶中制备了富含 Wi-A 的提取物 (Wi-AREAL)。对 Wi-AREAL (0.05-0.1%) 处理的人宫颈癌细胞（HeLa 和 ME-180）的实验分析包括活力、细胞凋亡、细胞周期、迁移、侵袭以及分子表达水平（mRNA 和蛋白质）的评估。与这些表型相关的标记。我们发现 Wi-AREAL 导致 p21WAF1 上调和参与细胞周期进程的几种蛋白质（CDK1、Cyclin B、pRb）介导的生长停滞。此外，Wi-AREAL 治疗激活了细胞凋亡信号传导，表现为 PARP-1 和 Bcl-2 水平降低、procaspase-3 增加和细胞色素 C 升高。此外，用无毒的低浓度 (0.01%) Wi-AREAL 治疗细胞抑制迁移和侵袭以及 EMT（上皮间质转化）信号传导。通过结合计算和实验方法，我们证明了 Wi-A 和 Wi-AREAL 作为 Survivin 天然抑制剂的潜力，这可能有助于癌症治疗。