Abstract

Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells. This effect was mediated by caspase activation, mainly caspase-2, and was partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo. Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM. What's new? Synthetic cannabinoids may help thwart multiple myeloma, according to new results. The hematopoietic system expresses high levels of the cannabinoid receptor CB2, but it is not known whether cannabinoids can be used to hinder hematologic cancers. In this study, the authors demonstrated that cannabinoids induced apoptosis in multiple myeloma cell lines without harming normal cells, including hematopoietic stem cells. They explored the mechanisms behind this apoptosis boost, showing that caspase activation and ceramide accumulation both play a role. When they treated mice with a cannabinoid compound, they successfully stifled plasmacytoma growth. Thus, cannabinoids could prove a useful therapy for multiple myeloma.