cannabigerol and Melanoma

During solid tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via tumor-secreted cytokines such as colony-stimulating factor 1 (CSF-1). Therefore, the depletion of tumor-secreted cytokines is a leading anticancer strategy. Here, we found that CSF-1 secretion by melanoma cells is decreased following treatment with Cannabis extracts. Cannabigerol (CBG) was identified as the bioactive cannabinoid responsible for the effects. Conditioned media from cells treated with pure CBG or the high-CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation. Tumor-bearing mice treated with CBG presented reduced tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of CBG and αPD-L1 was more effective in reducing tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for CBG in modulating the TME and enhancing immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of tumors with elevated CSF-1 expression.

Topics: Animals; Cytokines; Macrophage Colony-Stimulating Factor; Melanoma; Mice; Myeloid Cells; Tumor Microenvironment

UV radiation inducing mutations in melanocytes might cause melanoma. As changes in lipid composition and metabolism are associated with many types of cancer including skin cancer, we aimed to evaluate the effects of two phytocannabinoids cannabidiol (CBD) and cannabigerol (CBG), on changes in phospholipid and ceramide (CER) profiles induced by UVA irradiation in human melanocytes and melanoma. UVA radiation caused a significant up-regulation PC, PI and SM species and decrease of CERs content in both types of cells, while up-regulation of PEo was only observed in melanocytes. Exposure of UVA-irradiated melanocytes or melanoma cells to CBD and/or CBG led to significant decrease in relative content of PC, PI and SM specie; however, this effect was more pronounced in cancer cells. Interestingly, only in UVA-irradiated melanocytes and not in melanoma, PEo content was lowered after CBD treatment, while CBG led to additional up-regulation of PEo species. CBD and CBG used together caused decrease of zeta potential, inhibiting PS externalization, and different changes in relative contents of CER and SM species of irradiated and non-irradiated melanoma cells. Obtained results are quite promising due to CBD and CBG abilities to partial reverse pro-cancerogenic changes in phospholipid and CER profiles induced by UVA.

Topics: Cannabidiol; Humans; Melanocytes; Melanoma; Phospholipids; Ultraviolet Rays