“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

“Despite the targeted- and immunotherapies used in the past decade, survival rate among patients with metastatic melanoma remains low, therefore, melanoma is responsible for the majority of skin cancer-related deaths.

The ongoing investigation of natural antitumor agents, the nonpsychoactive cannabinoid, cannabigerol (CBG) found in Cannabis sativa is emerging as a promising candidate. CBG offers a potential therapeutic role in the treatment of melanoma demonstrating cell growth inhibition in some tumors. Its low water solubility and bioavailability hinder the potential effectiveness. To address these challenges, a modified CBG, namely LE-127/2 was synthesized by Mannich-type reaction.

The aim was to investigate the effect of this novel compound on cell proliferation as well as the mechanism of cell death with a particular focus on autophagy and apoptosis.

Human cutan melanoma cell lines, WM35, A2058 and WM3000 were utilized for the present study. Cell proliferation of the cells after the treatment with LE-127/2, parent CBG or vemurafenib was assessed by Cell Titer Blue Assay. Cells were treated with a 1.25-80 µM of the above-mentioned compounds, and it was found that at 20 μM of all drugs showed a comparable effective inhibition of cell proliferation, however, vemurafenib and CBG proved to be more effective than LE-127/2. In addition, clonogenic cell survival assays were performed to examine the inhibitory effect of LE-127/2 on the colony formation ability of melanoma cell lines.

Cells treated with 20 µM of LE-127/2 for 14 days showed about a 50% suppression of clonogenic cell survival. LE-127/2 exerted the most intensive inhibition on A2058 cell colonies. Furthermore, notably, LDH cytotoxicity assay performed on HaCaT cell line, proved LE-127/2 to be cytotoxic only at higher concentration, such as 80 μM, while the parent CBG was cytotoxic at concentration as low as 5 μM, suggesting that the new CBG derivative as a drug candidate may be applied in human pharmacotherapy without causing a substantial damage in intact epidermal cells. Analysis of protein expression revealed the impact of LE-127/2 on the expression of basic proteins (LC-3, Beclin-1 and p62) involved in the process of autophagy in the three different melanoma cell lines studied. Elevated expression of these proteins was detected as a result of LE-127/2 (20 µM) treatment. LE-127/2 also induced the expression of some proteins involved in apoptosis, and it is particularly noteworthy the increased level of cleaved PARP.

Based on the results obtained, it can be concluded that LE-127/2 induced autophagy could lead to the inhibition of cell proliferation and death in melanoma cells.”

https://pubmed.ncbi.nlm.nih.gov/39357769/

https://www.sciencedirect.com/science/article/pii/S0928098724002331?via%3Dihub

“Malignant melanoma (MM) continues to claim millions of lives around the world due to its limited therapeutic alternatives. Photodynamic therapy (PDT) has gained popularity in cancer treatment due it increased potency and low off-target toxicity. Studies have pointed out that the heterogeneity of MM tumours reduces the efficacy of current therapeutic approaches, including PDT, leading to high chances of recurrences post-treatment.

Accumulating evidence suggests that cannabidiol (CBD), a non-psychoactive derivative of cannabis, can synergise with various anticancer agents to increase their efficacy. However, CBD demonstrates low bioavailability, which is attributed to factors relating to poor water compatibility, poor absorption and rapid metabolism. Nanotechnology offers tools that address these issues and enhance the biological efficiency and targeted specificity of anticancer agents. Herein, we highlighted the standard therapeutic modalities of MM and their pitfalls, as well as pointed out the need for further investigation into PDT combination therapy with CBD.”

https://pubmed.ncbi.nlm.nih.gov/39074910/

“Accruing evidence suggests that CBD holds potential for inhibiting angiogenesis, metastasis, as well as prevents cellular proliferation by inducing cell death in cancer cells, thus counteracting metastasis.’

https://onlinelibrary.wiley.com/doi/10.1002/jbio.202400191

“Background: Ultraviolet-A radiation (UVA) contributes to photoaging/photocarcinogenesis by generating inflammation and oxidative damage. Current photoprotective strategies are limited by availability/utilization of UVA filters, highlighting an unmet need. Cannabidiol (CBD), having anti-inflammatory/antioxidant properties via regulation of NFR-2, HMOX1, and PPAR-y, could potentially mitigate damage from UVA exposure.

Objective/methods: Prospective, single-center, pilot clinical trial (NCT05279495). Nineteen participants applied nano-CBD (nCBD) or vehicle (VC) cream to randomized, blinded buttock sites twice-daily for 14-days, then treated sites were irradiated with ≤3x UVA minimal erythema dose. After 24-hours, punch biopsies were obtained for histology, immunohistochemistry, real-time PCR.

Results: At 24-hours, 21% of participants had less observed erythema on CBD-treated skin than VC skin. Histologically, nCBD-treated skin had reduced UVA-induced epidermal hyperplasia than VC (p=0.01). Immunohistochemistry detected reduced cytoplasmic/nuclear 8-oxo-guanine glycosylase 1 staining in nCBD-treated skin compared to VC (p<0.01). Quantitative mtDNA PCR demonstrated UVA-induced deletion of ND4 (proxy:4977bp deletion; p=0.003) and ND1 (proxy:3895bp deletion; p=0.002) were significantly reduced by in vivo nCBD treatment compared to VC.

Limitations: Sample size.

Conclusion: Topically applied nCBD cream reduced UVA-induced formation of a frequent mutagenic nuclear DNA base lesion and protected against mtDNA mutations associated with UVA-induced skin aging. This trial is the first to identify UV-protective capacity of CBD-containing topicals in humans.”

https://pubmed.ncbi.nlm.nih.gov/39025264/