Cannabinoids as Modulators of Cell Death: Clinical Applications and Future Directions.

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“Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic cannabinoids mimic the effects of endocannabinoids.

In recent years, a growing interest has been dedicated to the study of cannabinoids properties for their analgesic, antioxidant, anti-inflammatory and neuroprotective effects. In addition to these well-recognized effects, various studies suggest that cannabinoids may affect cell survival, cell proliferation or cell death. These observations indicate that cannabinoids may play an important role in the regulation of cellular homeostasis and, thus, may contribute to tissue remodelling and cancer treatment.

For a long time, the study of cannabinoid receptor signalling has been focused on the classical adenylyl cyclase/cyclic AMP/protein kinase A (PKA) pathway. However, this pathway does not totally explain the wide array of biological responses to cannabinoids. In addition, the diversity of receptors and signalling pathways that endocannabinoids modulate offers an interesting opportunity for the development of specific molecules to disturb selectively the endogenous system.

Moreover, emerging evidences suggest that cannabinoids ability to limit cell proliferation and to induce tumour-selective cell death may offer a novel strategy in cancer treatment.

This review describes the main properties of cannabinoids in cell death and attempts to clarify the different pathways triggered by these compounds that may help to understand the complexity of respective molecular mechanisms and explore the potential clinical benefit of cannabinoids use in cancer therapies.”

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Regulation of Cell Surface CB2 Receptor during Human B Cell Activation and Differentiation.

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“Cannabinoid receptor type 2 (CB2) is the primary receptor pathway mediating the immunologic consequences of cannabinoids.

We recently reported that human peripheral blood B cells express CB2 on both the extracellular membrane and at intracellular sites, where-as monocytes and T cells only express intracellular CB2. To better understand the pattern of CB2 expression by human B cells, we examined CD20+ B cells from three tissue sources.

Both surface and intracellular expression were present and uniform in cord blood B cells, where all cells exhibited a naïve mature phenotype (IgD+/CD38Dim). While naïve mature and quiescent memory B cells (IgD/CD38) from tonsils and peripheral blood exhibited a similar pattern, tonsillar activated B cells (IgD/CD38+) expressed little to no surface CB2.

We hypothesized that regulation of the surface CB2 receptor may occur during B cell activation. Consistent with this, a B cell lymphoma cell line known to exhibit an activated phenotype (SUDHL-4) was found to lack cell surface CB2 but express intracellular CB2.

Furthermore, in vitro activation of human cord blood resulted in a down-regulation of surface CB2 on those B cells acquiring the activated phenotype but not on those retaining IgD expression. Using a CB2 expressing cell line (293 T/CB2-GFP), confocal microscopy confirmed the presence of both cell surface expression and multifocal intracellular expression, the latter of which co-localized with endoplasmic reticulum but not with mitochondria, lysosomes, or nucleus.

Our findings suggest a dynamic multi-compartment expression pattern for CB2 in B cells that is specifically modulated during the course of B cell activation.”

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A Science Based Evaluation of Cannabis and Cancer

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“The irritant properties of all smoke will naturally tend to promote a pro-inflammatory immune response with the corresponding production of potentially carcinogenic free radicals. However, cannabis promotes immune deviation to an anti-inflammatory Th2 response via immune-system specific CB2 receptors. Thus, the natural pharmacological properties of marijuana’s cannabinoids, that are not present in tobacco smoke, would minimize potential irritant initiated carcinogenesis. In contrast, the pharmacological activities of tobacco smoke would tend to amplify its carcinogenic potential by inhibiting the death of genetically damaged cells. Together these observations support the epidemiological study of the Kaiser Foundation that did not find cannabis smoking to be associated with cancer incidence. Additionally, the demonstrated cancer killing activities of cannabinoids has been ignored. Cannabinoids have been shown to kill some leukemia and lymphoma, breast and prostate, pheochromocytoma, glioma and skin cancer cells in cell culture and in animals.”

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Potentiation of cannabinoid-induced cytotoxicity in Mantle Cell Lymphoma through modulation of ceramide metabolism

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“Ceramide accumulation is a widely described event in cancers after various treatments.

Ceramide levels are elevated in Mantle Cell Lymphoma (MCL) cells following treatment with cannabinoids.

In previous publications we and others observed that induction of ceramide accumulation by cannabinoids leads to apoptosis in MCL, glioma and pancreatic cancer.

Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA).

Our findings suggest that R-MA induces cell death in MCL via CB1-mediated upregulation of the de novo ceramide synthesis pathway.

This is the first study showing that the cytotoxic effect of a cannabinoid can be enhanced by modulation of ceramide metabolism.

The results suggest that interference with ceramide conversion may provide a tool to enhance the targeted cell death-promoting effects of cannabinoids in MCL and other malignant lymphomas overexpressing the CB1 receptor.

Cannabinoids have been suggested as a new non-toxic therapeutic option for cancer treatment.”

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Cannabinoid receptors in mantle cell lymphoma

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“Mantle cell lymphoma (MCL) is a non-curable B cell lymphoma that in several independent studies have been shown to express higher levels of CB1 and CB2 than non-malignant B cells.

The endocannabinoid system is dysregulated in many types of cancer and is involved in the regulation of survival and proliferation of cancer cells and cancer stem cells, in cancer metabolism, as well as in pro-metastatic events such as angiogenesis, migration and invasion.

Previous in vitro studies of MCL cell lines and primary ex vivo isolated tumor cells have demonstrated that high concentrations of cannabinoid receptor ligands induced proliferation arrest and programmed cell death.

All together, the data suggest that perturbations in the endocannabinoid system participate in the regulation of multi-functional cell responses regarding proliferation, migration and cell death control.

Therefore, it can be concluded that further studies on pharmacological modulation of endocannabinoid accumulation and/or signaling offers an interesting option for novel anti-lymphoma therapy.”

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Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma.

“We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)).

In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated.

The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.”

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Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma.

“We have earlier reported overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma (MCL), a B cell non-Hodgkin lymphoma.

In this study, treatment with cannabinoid receptor ligands caused a decrease in viability of MCL cells, while control cells lacking CB1 were not affected.

Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.”

“In conclusion, we have found that cannabinoid receptor ligands induce decreased viability, growth suppression and cell death by apoptosis in MCL cells, which express high levels of the CB1 receptor and moderate levels of CB2.

The current results in vitro suggest that CB1/CB2 ligands should be considered as agents for the treatment of MCL.”

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Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation.

“Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL).

In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type.

Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.”

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The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas.

“The initiating oncogenic event in mantle cell lymphoma (MCL) is the translocation of cyclin D1, t(11;14)(q13;q32). However, other genetic aberrations are necessary for an overt lymphoma to arise. Like other B cell lymphomas, MCL at some points during the oncogenesis is dependent on interactions with other cells and factors in the microenvironment.

The G protein coupled receptors cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed at low levels on non-malignant lymphocytes and at higher levels in MCL and other lymphoma subtypes.

In this review we give an overview of what is known on the role of the cannabinoid receptors and their ligands in lymphoma as compared to non-malignant T and B lymphocytes.

In MCL cannabinoids mainly reduce cell proliferation and induce cell death.

Importantly, our recent findings demonstrate that cannabinoids may induce either apoptosis or another type of programmed cell death, cytoplasmic vacuolation/paraptosis in MCL.”

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

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