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Title: Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.
Authors: Barbado, M Victoria
Medrano, Mayte
Caballero-Velázquez, Teresa
Álvarez-Laderas, Isabel
Sánchez-Abarca, Luis Ignacio
García-Guerrero, Estefania
Martín-Sánchez, Jesús
Rosado, Iván Valle
Piruat, José Ignacio
Gonzalez-Naranjo, Pedro
Campillo, Nuria Eugenia
Páez, Juan Antonio
Pérez-Simón, José Antonio
Keywords: apoptosis;cannabinoids;caspases;ceramides;multiple myeloma
metadata.dc.subject.mesh: Animals
Antineoplastic Agents
Caspase 2
Cell Line, Tumor
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-akt
Receptor, Cannabinoid, CB2
Signal Transduction
bcl-X Protein
Issue Date: 10-Nov-2016
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.
metadata.dc.identifier.doi: 10.1002/ijc.30483
Appears in Collections:Producción 2020

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