In the current study, we examined the effect of the non-psychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of EL-4, Jurkat or Molt-4 cells to cannabidiol in vitro led to a significant reduction in cell viability and the induction of apoptosis. Furthermore, in vivo cannabidiol treatment of EL-4-bearing mice led to a significant decrease in tumor burden and an increase in apoptotic tumors. Cannabidiol-induced apoptosis was inhibited by the CB2-selective antagonist and not by CB1-selective or VR1-selective antagonists. Exposure to cannabidiol led to the activation of a number of caspases, including caspase-8, caspase-9, and caspase-3, and to cleavage of PARP. In addition, the level of full-length Bid was decreased following exposure to cannabidiol, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome C. Interestingly, cannabidiol exposure led to an increase in ROS production and cannabidiol-induced apoptosis could be blocked by treatment with the ROS scavenger, α-tocopherol and the NADPH oxidase inhibitor, DPI. Examination of the expression of NADPH oxidases revealed that cannabidiol exposure led to the upregulation of p22phox and NOX4. In addition, cannabidiol exposure led to a decrease in the levels of p-ERK, p-JNK and p-p38 MAPK, which could be blocked by treatment with a CB2-selective antagonist or α-tocopherol. Together, the results from this study demonstrate that cannabidiol is a potent inducer of apoptosis in leukemia and that this mechanism may be related to the regulation of NAPDH oxidases and the production of reactive oxygen species.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]