cannabidiol and Liver-Neoplasms

Plant-derived extracellular vesicles (EVs) have been the topic of interest in recent years due to their proven therapeutic properties. Intact or manipulated plant EVs have shown antioxidant, anti-inflammatory, and anti-cancerous activities as a result of containing bioactive metabolites and other endogenous molecules. Less is known about the EV efficacy with high levels of bioactive secondary metabolites derived from medicinal or non-edible plants. Numerous data suggest the functionality of Cannabis sativa extract and its phytocannabinoids in cancer treatment. Here, two chemotypes of cannabis with different levels of D-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were selected. EVs were isolated from each chemotype via differential ultracentrifugation. HPLC analysis was illustrative of the absence of THC in EVs derived from both plants. Therefore, two types of EVs were classified according to their CBD content into high- (H.C-EVs) and low-CBD EVs (L.C-EVs). Electron microscopy and DLS showed both cannabis-derived EVs (CDEVs) can be considered as exosome-like nanovesicles. Cytotoxicity assay showed that H.C-EVs strongly decreased the viability of two hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh-7, in a dose and time-dependent manner compared with L.C-EVs. H.C-EVs had no significant effect on HUVECs normal cell growth. The finding showed that the H.C-EVs arrested the G0/G1 phase in the cell cycle and significantly induced cell death by activating mitochondrial-dependent apoptosis signaling pathways in both HCC cell lines. Altogether, the current study highlights that CDEVs can be an ideal natural vehicle for bioactive phytocannabinoids and a promising strategy in cancer management.

Topics: Analgesics; Cannabidiol; Cannabinoid Receptor Agonists; Cannabis; Carcinoma, Hepatocellular; Dronabinol; Extracellular Vesicles; Humans; Liver Neoplasms

Tumour cell migration and adhesion constitute essential features of metastasis. G-protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells.. Adhesion and migration assays using the highly metastatic colon cancer cell line HCT116 and an in vivo assay of liver metastasis were performed. The GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells.. HCT116 cells showed a significant decrease in adhesion to endothelial cells and in migration after blockade with CID16020046 or cannabidiol. The inhibitory effects of CID16020046 or cannabidiol were averted by GPR55 siRNA knock down in cancer cells. The integrity of endothelial cell monolayers was increased after pretreatment of HCT116 cells with the antagonists or after GPR55 siRNA knockdown while pretreatment with lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, decreased integrity of the monolayers. LPI also induced migration in GPR55 overexpressing HCT116 cells that was blocked by GPR55 antagonists. In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol. Increased levels of LPI (18:0) were found in colon cancer patients when compared with healthy individuals.. GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis. © 2015 The British Pharmacological Society.

Topics: Animals; Azabicyclo Compounds; Benzoates; Cannabidiol; Cell Adhesion; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Humans; Liver Neoplasms; Lysophospholipids; Mice; Neoplasm Metastasis; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; RNA, Small Interfering