“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/

“Cannabis and its major cannabinoid cannabidiol (CBD) are reported to exhibit anticancer activity against skin tumors. However, the cytotoxic effects of other minor cannabinoids and synthetic CBD derivatives in melanoma are not fully elucidated. Herein, the antiproliferative activity of a panel of phytocannabinoids was screened against murine (B16F10) and human (A375) melanoma cells. CBD was the most cytotoxic natural cannabinoid with respective IC₅₀ of 28.6 and 51.6 μM. Further assessment of the cytotoxicity of synthetic CBD derivatives in B16F10 cells identified two bipiperidinyl group-bearing derivatives (22 and 34) with enhanced cytotoxicity (IC₅₀ = 3.1 and 8.5 μM, respectively). Furthermore, several cell death assays including flow cytometric (for apoptosis and ferroptosis) and lactate dehydrogenase (for pyroptosis) assays were used to characterize the antiproliferative activity of CBD and its bipiperidinyl derivatives. The augmented cytotoxicity of 22 and 34 in B16F10 cells was attributed to their capacity to promote apoptosis (as evidenced by increased apoptotic population). Taken together, this study supports the notion that CBD and its derivatives are promising lead compounds for cannabinoid-based interventions for melanoma management.”

https://pubmed.ncbi.nlm.nih.gov/38671925/

“In summary, a series of phytocannabinoids were evaluated for their antiproliferative effects against melanoma cells (B16F10 and A375) and CBD showed the most promising activity. In addition, chemical modifications by introducing a bipiperidinyl group in CBD resulted in a pair of CBD derivatives (22 and 34) with enhanced cytotoxicity on B16F10 and A375 cells. Furthermore, data from a panel of bioassays supported the notion that the enhanced antiproliferative effects of CBD and its bipiperidinyl derivatives were associated with their capacity to mediate programmed cell death such as apoptosis in B16F10 cells. Further studies on the anti-tumor effect of CBD and its bipiperidinyl derivatives with in vivo models are warranted to better understand their effectiveness in the potential development of melanoma management.”

https://www.mdpi.com/2076-3921/13/4/478