Targeting cannabinoid receptors in hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) represents a major health problem, accounting for 90% of primary liver cancer and the second cause of cancer-related death worldwide.1 The tumour predominantly occurs in cirrhotic livers following exposure to various risk factors, including hepatitis B and C virus infection, excessive alcohol intake and metabolic syndrome. The majority of patients are diagnosed at intermediate or advanced stages and are ineligible for curative treatment. Several mechanisms contribute to the initiation and progression of HCC, including chronic inflammation, DNA damage, epigenetic modifications, senescence, telomerase reactivation, chromosomal instability, neo-angiogenesis. However, despite advances in the comprehension of HCC biology, sorafenib remains the single drug approved for HCC treatment with a marginal improvement of overall survival in patients. Endocannabinoids comprise a family of lipidic ligands for two canonical ubiquitous cannabinoid receptors, CB1 and CB2, among which anandamide, a CB1 ligand catabolised by fatty acid amide hydrolase (FAAH), and 2-arachydonoylglycerol, a CB1/CB2 ligand degraded by monoacylglycerol lipase (MAGL), are best characterised.2 Both compounds also interact with non-cannabinoid receptors, transient receptor potential (TRP) channels or G protein-coupled receptor 55. The endocannabinoid system (ECS) has been identified as a pivotal regulator …