Sanguinarine inhibits melanoma invasion and migration by targeting the FAK/PI3K/AKT/mTOR signalling pathway

Context Sanguinarine (SAG) is the most abundant constituent of Macleaya cordata (Willd.) R. Br. (Popaceae). SAG has shown antimammary and colorectal metastatic effects in mice in vivo, suggesting its potential for cancer chemotherapy. Objective To determine the antimetastatic effect and underlying molecular mechanisms of SAG on melanoma. Materials and methods CCK8 assay was used to determine the inhibition of SAG on the proliferation of A375 and A2058 cells. Network pharmacology analysis was applied to construct a compound-target network and select potential therapeutic targets of SAG against melanoma. Molecular docking simulation was conducted for further analysis of the selected targets. In vitro migration/invasion/western blot assay with 1, 1.5, 2 mu M SAG and in vivo effect of 2, 4, 8 mg/kg SAG in xenotransplantation model in nude mice. Results The key targets of SAG treatment for melanoma were mainly enriched in PI3K-AKT pathway, and the binding energy of SAG to PI3K, AKT, and mTOR were -6.33, -6.31, and -6.07 kcal/mol, respectively. SAG treatment inhibited the proliferation, migration, and invasion ability of A375 and A2058 cells (p < 0.05) with IC50 values of 2.378 mu M and 2.719 mu M, respectively. It also decreased the phosphorylation levels of FAK, PI3K, AKT, mTOR and protein expression levels of MMP2 and ICAM-2. In the nude mouse xenograft model, 2, 4, 8 mg/kg SAG was shown to be effective in inhibiting tumour growth. Conclusions Our research offered a theoretical foundation for the clinical antitumor properties of SAG, further suggesting its potential application in the clinic.

Automated summary

This study revealed the antimetastatic effect of SAG on melanoma and identified the underlying molecular mechanisms through the inhibition of the PI3K-AKT signaling pathway. Results showed that SAG inhibited the proliferation, migration, and invasion of melanoma cells and effectively suppressed tumor growth in a xenograft model. These findings offer a theoretical foundation for the clinical application of SAG in antitumor therapy.