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

Abstract

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 μM 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 IC 50 values of 2.378 μM and 2.719 μM, 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.

VEGF Inhibitors Improve Survival Outcomes in Patients with Liver Metastases across Cancer Types—A Meta-Analysis

“…These agents may be aimed at targeting tumour hypoxia (e.g., targeting HIF1α pathways) or cell signalling pathways. Sanguinarine is one of such novel agents, which inhibits VEGF, induces AKT phosphorylation, and reduces angiogenesis [71,72].…”

CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance

“…The PI3K/AKT/mTOR signal to downstream proteins leads to the development of tumor resistance [129,130]. Also, the PI3K/AKT/mTOR pathway has been shown to play a crucial role in a variety of biological and physiological processes including cell survival and growth, and transcription and translation, which are implicated in the development of drug resistance [18,33,131].…”