title: Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo.
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.
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: M Victoria
authors: MV
authors: Barbado
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Mayte
authors: M
authors: Medrano
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Teresa
authors: T
authors: Caballero-Velázquez
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Isabel
authors: I
authors: Álvarez-Laderas
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Luis Ignacio
authors: LI
authors: Sánchez-Abarca
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Estefania
authors: E
authors: García-Guerrero
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Jesús
authors: J
authors: Martín-Sánchez
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: Iván Valle
authors: IV
authors: Rosado
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: José Ignacio
authors: JI
authors: Piruat
authors: Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors: Pedro
authors: P
authors: Gonzalez-Naranjo
authors: Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors: Nuria Eugenia
authors: NE
authors: Campillo
authors: Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors: Juan Antonio
authors: JA
authors: Páez
authors: Department of Hematology, Institute of Biomedicine of Sevilla (IBIS/CSIC), University Hospital Virgen del Rocío, Universidad de Sevilla, Spain.
authors: José Antonio
authors: JA
authors: Pérez-Simón
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D053143:Caspase 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013107:Sphingolipids / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002186:Cannabinoids; D002518:Ceramides; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D043885:Receptor, Cannabinoid, CB2; D013107:Sphingolipids; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt; D053143:Caspase 2
keywords: apoptosis; cannabinoids; caspases; ceramides; multiple myeloma