Proapoptotic Effect of Icariin on Human Ovarian Cancer Cells via the NF-κB/PI3K-AKT Signaling Pathway: A Network Pharmacology-Directed Experimental Investigation

Abstract

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.

Anti-Alzheimers molecular mechanism of icariin: Insights from gut microbiota and metabolome combined network pharmacology

“…The results revealed that the therapeutic impact of ICA on AD may be implicated in a variety of signaling pathways including the PI3K-Akt signaling pathway, sphingolipid signaling pathway and NF-κB signaling pathway, consistent with previous studies [39]. In ovarian cancer, ICA has been proved to have a therapeutic effect via the PI3K-Akt signaling pathway and the NF-κB signaling pathway [40]. Consistent with the metabolomics results, ICA was speculated to affect the sphingolipid signaling pathway by PRKCA/TNF/TP53/AKT1/RELA/NFKB1 (Figure 6F).…”

Synthesis of peiminine derivatives and its effect on A549 lung cancer‐bearing mice

“…IκB is an inhibitor of NF‐κB, and inhibition of IκB can promote the activation of NF‐κB. NF‐κB is involved in the formation, invasion, metastasis, and angiogenesis of NSCLC (Gao et al., 2022). At the same time, it can affect the expression level of Bcl‐2.…”

Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology

“…The results revealed that the therapeutic effect of ICA on AD may be mediated via a variety of signaling pathways, including the PI3K-Akt signaling pathway, sphingolipid signaling pathway, and NF-κB signaling pathway, consistent with previous studies [ 40 ]. ICA has been reported to have a therapeutic effect on ovarian cancer by regulating the PI3K-Akt signaling pathway and NF-κB signaling pathway [ 41 ]. Consistent with the metabolomics results, ICA was hypothesized to affect the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis (Fig.…”