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“Cannabinoid receptor-2 (CB2) is expressed dominantly in the immune system, especially on plasma cells.
Cannabinergic ligands with CB2 selectivity emerge as a class of promising agents to treat CB2-expressing malignancies without psychotropic concerns.
In this study, we found that CB2 but not CB1 was highly expressed in human multiple myeloma (MM) and primary CD138+ cells.
Thus, targeting CB2 may represent an attractive approach to treat cancers of immune origin.”
“Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the accumulation of a monoclonal PC population in the bone marrow (BM).
Cannabidiol (CBD) is a non-psychoactive cannabinoid with antitumoural activities, and the transient receptor potential vanilloid type-2 (TRPV2) channel has been reported as a potential CBD receptor.
TRPV2 activation by CBD decreases proliferation and increases susceptibility to drug-induced cell death in human cancer cells.
However, no functional role has been ascribed to CBD and TRPV2 in MM. In this study, we identified the presence of heterogeneous CD138+TRPV2+ and CD138+TRPV2- PC populations in MM patients, whereas only the CD138+ TRPV2- population was present in RPMI8226 and U266 MM cell lines.
Because bortezomib (BORT) is commonly used in MM treatment, we investigated the effects of CBD and BORT in CD138+TRPV2- MM cells and in MM cell lines transfected with TRPV2 (CD138+TRPV2+).
These results showed that CBD by itself or in synergy with BORT strongly inhibited growth, arrested cell cycle progression and induced MM cells death by regulating the ERK, AKT and NF-κB pathways with major effects in TRPV2+ cells.
These data provide a rationale for using CBD to increase the activity of proteasome inhibitors in MM.”
“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.”
“Renal cell carcinoma (RCC) is a common urologic tumor with a poor prognosis.
Cannabinoid receptor 1 (CB1), which is a G protein-coupled receptor, has recently been reported to participate in the genesis and development of various cancers.
However, the exact role of CB1 in RCC is unknown. The aim of this study was to determine the role of CB1 in RCC cell lines and RCC prognosis, thus underlying its potential as a therapeutic target.
CB1 expression is functionally associated to cellular proliferation, apoptosis, and invasion ability of RCC.
Our data suggest that CB1 might be a potential target for RCC clinical therapy.”
“Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis.
It has also been reported that these compounds inhibit tumor cell spreading.
Here, we evaluated the effect of cannabinoids on matrix metalloproteinase (MMP) expression and its effect on tumor cell invasion.
Local administration of Δ9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas generated in mice.
This cannabinoid-induced inhibition of MMP-2 expression in gliomas.
As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity.
As selective CB2 receptor activation to mice has been shown to inhibit the growth and angiogenesis of gliomas, skin carcinomas and melanomas, our observations further support the possibility of finding cannabinoid-based antitumoral strategies devoid of nondesired psychotropic side effects.”
http://cancerres.aacrjournals.org/content/68/6/1945
“Chemotherapy-induced nausea and vomiting (CINV) is a complex pathophysiological condition and consists of two phases.
The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT) from the enterochromaffin cells in the gastrointestinal tract (GIT), while the delayed phase is a consequence of release of substance P (SP) in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV.
Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites) in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS).
No single antiemetic is currently available to completely prevent both phases of CINV.
The standard antiemetic regimens include a 5-HT₃ antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant) for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients.
Cannabinoids such as D⁸-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients.
Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists.
Cannabinoids (both phyto-derived and synthetic) behave as agonist antiemetics via the activation of cannabinoid CB₁ receptors in both the brainstem and the ENS emetic loci.
An endocannabinoid antiemetic tone may exist since inverse CB₁ agonists (but not the corresponding silent antagonists) cause nausea and vomiting.”
“Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered.
Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases.
Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function.
Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders.
At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses.
Therefore, DC are potential targets for cannabinoid-mediated modulation.
Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.”
“Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide.
Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells.
In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells.
BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2 ), but not cannabinoid receptor type 1 (CB1 ). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery.
It is known that BCPO alters several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties.
The selective activation of CB2 may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB1 stimulation. Thus, BCP as selective CB2 activator may be taken into account as potential natural analgesic drug.
Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology.
This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.”
https://www.ncbi.nlm.nih.gov/pubmed/27696789
“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934
“The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis.
Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects.
Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat.
CONCLUSIONS AND INFERENCES:
5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose.
Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.”
“Anti-neoplastic activity induced by cannabinoids has been extensively documented for a number of cancer cell types; however, this topic has been explored in gastric cancer cells only in a limited number of approaches.
SIGNIFICANCE:
Through a comparative approach, our results support and confirm the therapeutic potential that cannabinoid receptor agonists exert in gastric cancer cells and open possibilities to use cannabinoids as part of a new gastric cancer therapy.”