* Corresponding author; email: wai.liu@icr.ac.uk.

9-tetrahydrocannabinol (THC) is the active metabolite of cannabis.

THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear.

We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukaemic cell lines, and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors, and utilised combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process.

We have shown that THC is a potent inducer of apoptosis, even at 1X IC50 concentrations, and as early as six hours after exposure to the drug. These effects were seen in leukaemic cell lines (CEM, HEL-92 and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin.

One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the MAPK signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.