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 IC₅₀ 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.

Keywords:

• Network pharmacology
• molecular docking
• metastasis
• adhesion

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Correction

Acknowledgments

This work was supported by the National Natural Science Foundation (81672458, 82003850), the Grants from the Science and Technology Planning Project of Sichuan Province (2021JDTD0003, 2022NSFSC0576，2022YFS0631，2022YFS0626, 2022YFS0625), the Sichuan Province Post Doctoral Fund Special Assistance Program (202027)，the Science and Technology Cooperation Project of Gulin County People's and Hospital and Southwest Medical University Affiliated Hospital (2022GLXNYDFY12)，Suining First People's Hospital Southwest Medical University Cooperation Project (2022SNXNYD02), Office of science & technology and talent work of Luzhou (2022-JYJ-138) and the Youth Program of Southwest Medical University (2021ZKQN098).

Author contributions

M. Lü and S. Liang designed the study and checked the data. X. Qi, Y. Chen and S. Liu performed the experimental work and conducted original data analysis. Li. Liu provided the experimental assistance. X. Qi and Y. Chen wrote the first draft of the manuscript. M. Lü and S. Liang provided their valuable guidance and suggestions. Y. Chen and S. Liang revised the manuscript. X. Qi, M. Lü and S. Liang were responsible for funding acquisition. The manuscript has been read and approved by all the authors and each author believes that the manuscript represents honest work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/13880209.2023.2210885).