Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.

Barbado, M VictoriaMedrano, MayteCaballero-Velazquez, TeresaAlvarez-Laderas, IsabelSanchez-Abarca, Luis IgnacioGarcia-Guerrero, EstefaniaMartin-Sanchez, JesusRosado, Ivan VallePiruat, Jose IgnacioGonzalez-Naranjo, PedroCampillo, Nuria EugeniaPaez, Juan AntonioPerez-Simon, Jose Antonio2023-01-252023-01-252016-12-14Barbado MV, Medrano M, Caballero-Velázquez T, Álvarez-Laderas I, Sánchez-Abarca LI, García-Guerrero E, et al. Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo. Int J Cancer. 2017 Feb 1;140(3):674-685.http://hdl.handle.net/10668/10558Although 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.enapoptosiscannabinoidscaspasesceramidesmultiple myelomaAnimalsAntineoplastic AgentsApoptosisCannabinoidsCaspase 2Cell Line, TumorCeramidesHumansMiceMice, Inbred NODMice, SCIDMultiple MyelomaMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-aktReceptor, Cannabinoid, CB2Signal TransductionSphingolipidsbcl-X ProteinCannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.research article27778331Restricted AccessCannabinoidesApoptosisCélulasMelfalánReceptor cannabinoide CB2NeoplasiasNeoplasias hematológicas10.1002/ijc.304831097-0215https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.30483