School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China.
Guangzhou University of Traditional Chinese Medicine, Huizhou Traditional Chinese Medicine Hospital, Huizhou, Guangdong 516001, P. R. China.
Am J Chin Med. 2022;50(2):589-619. doi: 10.1142/S0192415X22500239. Epub 2022 Feb 3.
Based on network pharmacology tools and public bioinformatics databases, the pharmacodynamic target and key mechanism of icariin (ICA) in the treatment of ovarian cancer (OC) were identified and experimentally verified. Our previous research showed that TNF, MMP9, STAT3, PIK3CA, ERBB2, MTOR, IL2, PTGS2, KDR and F2 are important targets of ICA in the treatment of OC. TNF, as a hub gene in tumor tissues, was associated with poor prognosis. ICA acted on OC mainly through the biological functions of various kinases, and the pathway with the highest accuracy ([Formula: see text]-value) was PI3K. Meanwhile, we observed a close upstream and downstream relationship between NF-[Formula: see text]B and the Pl3K-AKT pathway. This study further verified the mechanism of ICA in promoting apoptosis of SKOV3 cells through the NF-[Formula: see text]B signaling pathway and the tandem relationship between NF-[Formula: see text]B and the Pl3K-AKT pathway. The assay results demonstrated that ICA can promote the apoptosis of SKOV3 cells as indicated by the proapoptotic markers Bax, Bcl-xl and Caspase-3 and the key factors of the NF-[Formula: see text]B signaling pathway (NF-[Formula: see text]Bp65, p-NF-[Formula: see text]Bp65, p-I[Formula: see text]B[Formula: see text] and I[Formula: see text]B[Formula: see text]. ICA can block the classical NF-[Formula: see text]B pathway by inhibiting I[Formula: see text]B[Formula: see text] phosphorylation and consequently blocking the activation of the NF-[Formula: see text]B pathway in SKOV3 cells. ICA can also promote apoptosis by blocking the activation of the NF-[Formula: see text]B pathway in SKOV3 cells via inhibition of NF-[Formula: see text]Bp65 nuclear translocation. After using a PI3K pathway inhibitor, we further discovered that ICA may reduce AKT signal transduction by inhibiting the level of Akt phosphorylation, resulting in a loss of PI3K/Akt-dependent activation of the NF-[Formula: see text]B pathway.
基于网络药理学工具和公共生物信息学数据库，鉴定并实验验证了淫羊藿苷（ICA）治疗卵巢癌（OC）的药效靶点和关键机制。我们之前的研究表明，TNF、MMP9、STAT3、PIK3CA、ERBB2、MTOR、IL2、PTGS2、KDR 和 F2 是 ICA 治疗 OC 的重要靶点。TNF 作为肿瘤组织中的一个枢纽基因，与预后不良有关。ICA 主要通过各种激酶的生物学功能作用于 OC，且准确率最高的通路为 PI3K。同时，我们观察到 NF-κB 与 Pl3K-AKT 通路之间存在密切的上下游关系。本研究进一步验证了 ICA 通过 NF-κB 信号通路促进 SKOV3 细胞凋亡的机制，以及 NF-κB 与 Pl3K-AKT 通路之间的串联关系。实验结果表明，ICA 可以通过促凋亡标志物 Bax、Bcl-xl 和 Caspase-3 以及 NF-κB 信号通路的关键因子（NF-κBp65、p-NF-κBp65、p-IκBα 和 IκBα）促进 SKOV3 细胞凋亡。ICA 可以通过抑制 IκBα磷酸化阻断经典 NF-κB 通路，从而阻断 SKOV3 细胞中 NF-κB 通路的激活。ICA 还可以通过抑制 NF-κBp65 核转位来阻断 SKOV3 细胞中 NF-κB 通路的激活，从而促进细胞凋亡。使用 PI3K 通路抑制剂后，我们进一步发现 ICA 可能通过抑制 Akt 磷酸化水平来减少 AKT 信号转导，从而导致 PI3K/Akt 依赖性 NF-κB 通路激活丧失。
