CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β

Abstract

Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial–mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Treatment of 6D breast cancer cells with CBD was able to significantly reduce migration and invasion, promoted the recovery of cell contacts, and reduced the expression of malignant markers. CBD was also able to increase sensitivity to anticancer agents doxorubicin and cisplatin in 6D cells by down-regulating the expression of resistance proteins [98]. In murine models of breast cancer, CBD reduced cell proliferation and overall tumour growth, as well as migration and invasion to reduce metastasis [97].…”

Anti-tumor effects of an ID antagonist with no observed acquired resistance

“…We note that the use of cannabidiol (CBD), which reduces Id1 transcription, has been reported to inhibit aggressive breast cancer cell behavior as a single agent 67 . This may in part reflect broad CBD activity against a variety of factors including β-catenin and protein kinase B (AKT) among others 68 .…”

Cannabidiol Suppresses Angiogenesis and Stemness of Breast Cancer Cells by Downregulation of Hypoxia-Inducible Factors-1α

“…CBD reduced the proliferation rate at higher CBD concentrations in all breast cancer cell lines, but not in the normal breast cells. It was reported that the viability of MCF7 cells at a specific concentration of CBD (10 μM) was reduced to 90% by CBD and this occurred through interaction with the CB1 receptor [ 19 ]. Although it is known that the relationship between CB receptors and the anti-cancer effect of CBD has been uncertain, it was reported that CBD downregulated the CB1 receptor level through the low expression of CNR1 and could reduce the viability of MCF7 cells [ 19 ].…”

“…CBD also downregulated the expression of EMT markers such as Slug and Vimentin. CBD might cause breast cancer cells to be less aggressive by mesenchymal reversion to an epithelial phenotype via IL-1β/IL-1R/β-catenin, E-cadherin/β-catenin complex relocalization, and other protein markers of malignancy [ 19 ]. Thus, it could be understood that CBD can inhibit the aggressiveness of breast cancer and be sensitized to more aggressive breast cancer cells by regulating a variety of signaling pathways and immunologic factors related to malignancy as well as Src/VHL/HIF-1α signaling.…”