title: Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration.
abstract: Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with Δ9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggesting their use in combination therapy. In the current study, we evaluated the effects of THC alone and in combination with CBD in MM cell lines. We found that CBD and THC, mainly in combination, were able to reduce cell viability by inducing autophagic-dependent necrosis. Moreover, we showed that the CBD-THC combination was able to reduce MM cells migration by down-regulating expression of the chemokine receptor CXCR4 and of the CD147 plasma membrane glycoprotein. Furthermore, since the immuno-proteasome is considered a new target in MM and also since carfilzomib (CFZ) is a new promising immuno-proteasome inhibitor that creates irreversible adducts with the β5i subunit of immuno-proteasome, we evaluated the effect of CBD and THC in regulating the expression of the β5i subunit and their effect in combination with CFZ. Herein, we also found that the CBD and THC combination is able to reduce expression of the β5i subunit as well as to act in synergy with CFZ to increase MM cell death and inhibits cell migration. In summary, these results proved that this combination exerts strong anti-myeloma activities.
authors: School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.
authors: Massimo
authors: M
authors: Nabissi
authors: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors: Maria Beatrice
authors: MB
authors: Morelli
authors: Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
authors: Massimo
authors: M
authors: Offidani
authors: School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors: Consuelo
authors: C
authors: Amantini
authors: Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
authors: Silvia
authors: S
authors: Gentili
authors: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors: Alessandra
authors: A
authors: Soriani
authors: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors: Claudio
authors: C
authors: Cardinali
authors: Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
authors: Pietro
authors: P
authors: Leoni
authors: School of Pharmacy, Experimental Medicine Section, University of Camerino, Camerino, Italy.
authors: Giorgio
authors: G
authors: Santoni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers; D002186:Cannabinoids / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D002186:Cannabinoids; D039641:Integrin beta Chains; D009842:Oligopeptides; C084344:integrin beta5; C524865:carfilzomib
keywords: CBD; THC; carfilzomib; combination therapy; immuno-proteasome; multiple myeloma