“Melanoma represents one of the most aggressive forms of skin cancers, with advanced metastatic stages largely managed through chemotherapy. However, current therapeutic strategies remain limited by drug resistance and systemic toxicity. Cannabidiol (CBD), the primary nonpsychoactive constituent of Cannabis sativa, has recently attracted attention for its anticancer properties across multiple tumor types.

OBJECTIVES

This study aimed to explore the antitumor efficacy of CBD in melanoma and elucidate its underlying molecular mechanisms, with the goal of identifying novel therapeutic strategies to overcome resistance and reduce adverse effects associated with conventional treatments.

METHODS

The antiproliferative and pro-apoptotic effects of CBD were assessed in vitro using MTS, EdU, Transwell invasion, and flow cytometry. In vivo efficacy was evaluated using a murine lung metastasis model. Potential CBD targets in melanoma were identified through network pharmacology and molecular docking, with a focus on peroxisome proliferator-activated receptor γ (PPARγ) and validation by western blotting and immunofluorescence. Integrated transcriptomic and genome-wide methylation analyses were performed to investigate epigenetic modifications induced by CBD. Co-immunoprecipitation and chromatin immunoprecipitation assays were employed to detect the interaction between PPARγ and ten-eleven translocation 1 (TET1), including their binding to promoter regions of downstream factors. Methylation-regulated target genes were further validated using qPCR and MeDIP PCR.

RESULTS

CBD significantly induced apoptosis and inhibited cell proliferation and invasion of melanoma cells in vitro, while reducing pulmonary metastasis in vivo. Pharmacological and molecular docking analyses, supported by protein-level validation, identified PPARγ as a critical mediator of CBD activity. Transcriptomic and methylation analyses revealed that CBD modulated global DNA methylation patterns, partly through the formation of a PPARγ-TET1 complex. This complex regulated the demethylation of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), a newly identified anticancer gene whose upregulation markedly enhanced melanoma cell apoptosis and suppressed proliferation.

CONCLUSIONS

CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ–TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326000127

“In summary, this study investigated molecular targets and mechanisms by which CBD suppresses melanoma progression, emphasizing its role in PPARγ activation and epigenetic regulation. These findings establish a mechanistic basis and provide candidate targets for future clinical application of CBD in melanoma treatment.”

“This study provides the first evidence that CBD inhibits melanoma progression by modulating gene methylation. The identification of LRSAM1 as a PPARγ-TET1-regulated tumor suppressor expands current understanding of epigenetic regulation in melanoma and highlights LRSAM1 as a viable therapeutic target.”

https://www.scilit.com/publications/50c9c0a6d08f7880cebb9c69a2c3fca7