- PMID:
- 27778331
- DOI:
- 10.1002/ijc.30483
- [PubMed - in process]
Int J Cancer. 2017 Feb 1;140(3):674-685. doi: 10.1002/ijc.30483. Epub 2016 Nov 10.
Barbado MV1, Medrano M1, Caballero-Velázquez T1, Álvarez-Laderas I1, Sánchez-Abarca LI1, García-Guerrero E1, Martín-Sánchez J1, Rosado IV1, Piruat JI1, Gonzalez-Naranjo P2, Campillo NE2, Páez JA2, Pérez-Simón JA1.
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.
© 2016 UICC.
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