In the current study, we examined whether
ligation of CB2 receptors would lead to induction of apoptosis in
tumors of immune origin and whether CB2 agonist could be used to treat such
cancers. Exposure of murine
tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (
THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis. Exposure of EL-4
tumor cells to the synthetic
cannabinoid HU-210 and the endogenous
cannabinoid anandamide led to significant induction of apoptosis, whereas exposure to WIN55212 was not effective. Treatment of EL-4
tumor-bearing mice with
THC in vivo led to a significant reduction in
tumor load, increase in
tumor-cell apoptosis, and increase in survival of
tumor-bearing mice. Examination of a number of human
leukemia and
lymphoma cell lines, including Jurkat, Molt-4, and Sup-T1, revealed that they expressed CB2 receptors but not CB1. These human
tumor cells were also susceptible to apoptosis induced by
THC,
HU-210,
anandamide, and the CB2-selective agonist
JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist
SR144528 partially reversed the
THC-induced apoptosis. Culture of primary
acute lymphoblastic leukemia cells with
THC in vitro reduced cell viability and induced apoptosis. Together, the current data demonstrate that CB2
cannabinoid receptors expressed on
malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel
anticancer agents to selectively target and kill
tumors of immune origin.