Casticin inhibits nasopharyngeal carcinoma growth by targeting phosphoinositide 3-kinase

Abstract

BackgroundCasticin, an isoflavone compound extracted from the herb Fructus Viticis, has demonstrated anti-inflammatory and anticancer activities and properties. The aim of this study was to investigate the effects and mechanisms of casticin in nasopharyngeal carcinoma (NPC) cells and to determine its potential for targeted use as a medicine.MethodsNPC cells were used to perform the experiments. The CCK‑8 assay and colony formation assays were used to assess cell viability. Flow cytometry was used to measure the cell cycle and apoptosis analysis (annexin V/PI assay). A three-dimensional (3D) tumour sphere culture system was used to characterize the effect of casticin on NPC stem cells. In silico molecular docking prediction and high-throughput KINOME scan assays were used to evaluate the binding of casticin to phosphoinositide 3-kinase (PI3K), including wild-type and most of mutants variants. We also used the SelectScreen assay to detect the IC50 of ATP activity in the active site of the target kinase. Western blotting was used to evaluate the changes in key proteins involved cell cycle, apoptosis, stemness, and PI3K/protein kinase B (AKT) signalling. The effect of casticin treatment in vivo was determined by using a xenograft mouse model.ResultsOur results indicate that casticin is a new and novel selective PI3K inhibitor that can significantly inhibit NPC proliferation and that it induces G2/GM arrest and apoptosis by upregulating Bax/BCL2 expression. Moreover, casticin was observed to affect the self-renewal ability of the nasopharyngeal carcinoma cell lines, and a combination of casticin with BYL719 was observed to induce a decrease in the level of the phosphorylation of mTORC1 downstream targets in BYL719-insensitive NPC cell lines.ConclusionCasticin is a newly emerging selective PI3K inhibitor with potential for use as a targeted therapeutic treatment for nasopharyngeal carcinoma. Accordingly, casticin might represent a novel and effective agent against NPC and likely has high potential for combined use with pharmacological agents targeting PI3K/AKT.

Casticin protected against neuronal injury and inhibited the TLR4/NF‐κB pathway after middle cerebral artery occlusion in rats

“…Casticin could dock to the protein crystal structure of PI3K to inhibit the activity of PI3K; casticin could form hydrogen bonds with PI3K at two amino acid sites, Val854 and Agr770, and a hydrophobic bond with PI3K at Val851. Thus, the PI3K/AKT pathway could be inhibited by casticin 28 . NF‐κB is the downstream pathway of PI3K/AKT 29 .…”

An Overview of the Potential Antineoplastic Effects of Casticin

“…The reduction in MMP-9 protein levels reserved the invasion abilities of the breast cancer cell lines. The findings in this particular research paper suggest that casticin has properties to inhibit the PI3K/Akt signaling pathway, preventing cell invasion and migration in various tumor cells, including breast cancer [48]. The Akt signaling pathway is crucial for regulating both tumorigenesis (the formation of a tumor) and the cell cycle.…”

“…Casticin is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, which is the predominant mechanism for its anticancer activity. Casticin can also upregulated in the Bax/Bcl-2 ratio through an increase in ROS generation in the mitochondria, as discussed in detail below [48]. The IC50 values, or half-maximal inhibitory concentrations, for available cell lines are also given.…”

“…The Akt signaling pathway is crucial for regulating both tumorigenesis (the formation of a tumor) and the cell cycle. The pathway is activated by a large number of receptor tyrosine kinases-for example, epidermal cell growth factor receptor (EGFR) and insulin-like growth factors (IFGRs)-with protein kinase B (PKB) being the central node that can be stimulated [48,53,54]. Casticin significantly inhibits cell viability by suppressing Akt activation in a concentration-dependent manner and also inhibits self-renewal and invasionary behaviors of cancer cells.…”

“…Casticin significantly inhibits cell viability by suppressing Akt activation in a concentration-dependent manner and also inhibits self-renewal and invasionary behaviors of cancer cells. Besides opioid receptors, casticin may also directly bind to several proteins, including estrogen receptors, threonine-protein kinase Pim-1 and reticuline oxidase, as revealed by docking studies [48,53]. As a result, casticin could be utilized as an antineoplastic drug for human breast cancers.…”