The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type‐2

Morelli, Maria Beatrice; Offidani, Massimo; Alesiani, Francesco; Discepoli, Giancarlo; Liberati, Sonia; Olivieri, Attilio; Santoni, Matteo; Santoni, Giorgio; Leoni, Pietro; Nabissi, Massimo

doi:10.1002/ijc.28591

Cited by 89 publications

(97 citation statements)

References 46 publications

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“…Interestingly, in addition to activating TRPV2, CBD also stimulated TRPV2 expression in this cell line. Finally, such TRPV2-dependent effects of CBD in malignant cell lines were extended by a similar demonstration of CBD-induced increases in chemosensitivity in a multiple myeloma cell line [111]. In both cases, TRPV2-mediated effects of CBD in malignant cells required moderate micromolar concentrations (≥20 μM) to achieve significant effects.…”

Section: Trp Channelsmentioning

confidence: 79%

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Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

425

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Trp Channelsmentioning

confidence: 79%

“…Blockade of the A 2A receptor in Parkinsonian rats abolished the motor deficits. The side effect profile was favorable owing to low A 2A receptor expression in other regions of the brain [111]. As CBD activates A 2A receptors, this interaction is unlikely to have any beneficial effect in PD.…”

Section: Cbd Receptor Targets In Movement Disordersmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

425

323

View full text Add to dashboard Cite

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“…The effect of CBD in reducing cell viability was previously studied [11] in the U266 (IC 50 = 19.8 μM) and in the RPMI (IC 50 = 22.4 μM) cell lines. In the present study, we treated U266 and RPMI cells with THC (up to 1 mM) for 72 h and percentage of cell viability was evaluated by the MTT assay.…”

Section: Resultsmentioning

confidence: 99%

“…THC and/or CBD were able to reduce cell proliferation and induce cell death in glioblastoma (GBM), lung and breast cancers, hepatocellular carcinoma and melanoma [4–10]. In addition, CBD has been shown to reduce viability, induce necrosis as well as synergize with bortezomib (BTZ) in reducing cell proliferation and cell survival pathways in multiple myeloma (MM) cell lines [11]. THC and CBD also show anti-inflammatory activities, by decreasing the release of pro-inflammatory cytokines (IFN-γ, IFN-β, IL-1 β, IL-6) and related transcription factors (such as NF-kB and STAT-3), in normal [12] and cancer cell lines, including MM [11].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, CBD has been shown to reduce viability, induce necrosis as well as synergize with bortezomib (BTZ) in reducing cell proliferation and cell survival pathways in multiple myeloma (MM) cell lines [11]. THC and CBD also show anti-inflammatory activities, by decreasing the release of pro-inflammatory cytokines (IFN-γ, IFN-β, IL-1 β, IL-6) and related transcription factors (such as NF-kB and STAT-3), in normal [12] and cancer cell lines, including MM [11]. Another important feature is that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells as well as CXCR4-mediated migration of immune cells [13].…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

et al. 2016

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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.

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Anticancer effect of minor phytocannabinoids in preclinical models of multiple myeloma

Aguzzi,

Zeppa,

Morelli

et al. 2024

BioFactors

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Multiple myeloma (MM) is a blood cancer caused by uncontrolled growth of clonal plasmacells. Bone disease is responsible for the severe complications of MM and is caused by myeloma cells infiltrating the bone marrow and inducing osteoclast activation. To date, no treatment for MM is truly curative since patients relapse and become refractory to all drug classes. Cannabinoids are already used as palliative in cancer patients. Furthermore, their proper anticancer effect was demonstrated in many cancer models in vitro, in vivo, and in clinical trials. Anyway, few information was reported on the effect of cannabinoids on MM and no data has been provided on minor phytocannabinoids such as cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and cannabidivarin (CBDV). Scientific literature also reported cannabinoids beneficial effect against bone disease. Here, we examined the cytotoxic activity of CBG, CBC, CBN, and CBDV in vitro in MM cell lines, their effect in modulating MM cells invasion toward bone cells and the bone resorption. Subsequently, according to the in vitro results, we selected CBN for in vivo study in a MM xenograft mice model. Results showed that the phytocannabinoids inhibited MM cell growth and induced necrotic cell death. Moreover, the phytocannabinoids reduced the invasion of MM cells toward osteoblast cells and bone resorption in vitro. Lastly, CBN reduced in vivo tumor mass. Together, our results suggest that CBG, CBC, CBN, and CBDV can be promising anticancer agents for MM.

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The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type‐2

Cited by 89 publications

References 46 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

Anticancer effect of minor phytocannabinoids in preclinical models of multiple myeloma

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