Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

Image result for Eur J Pharmacol.

“Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis.

Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies.

Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects.

The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer.

Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address.”

http://www.ncbi.nlm.nih.gov/pubmed/26852955

http://www.thctotalhealthcare.com/category/cancer/

Therapeutic Potential of Cannabinoids in Psychosis.

“Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treatment of schizophrenia has evolved.

The ECS represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes.

Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the type 1 cannabinoid receptor has been tested for the improvement of acute psychotic symptoms, as well as for the improvement of cognitive functions in schizophrenia.

Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase inhibitors has been proposed, and the antipsychotic properties of cannabidiol are currently being investigated in humans.

Unfortunately, for most of these trials that have focused on psychopathological and cognitive effects of cannabidiol, no published data are available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared with established antipsychotics.

In conclusion, several clinical trials targeting the ECS in acute schizophrenia have either been completed or are underway. Although publicly available results are currently limited, preliminary data indicate that selected compounds modulating the ECS may be effective in acute schizophrenia.

Nevertheless, so far, sample sizes of patients investigated are not sufficient to come to a final judgment, and no maintenance studies are available to ensure long-term efficacy and safety.”

http://www.ncbi.nlm.nih.gov/pubmed/26852073

http://www.thctotalhealthcare.com/category/schizophrenia/

A Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of Endocannabinoid 2-Arachidonoylglycerol and Higher Body Mass Index in Women.

“The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice.

The eCB system is over-active in human obesity.

Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system.

Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity.

In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects.”

http://www.ncbi.nlm.nih.gov/pubmed/26849214

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity.

“Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance.

The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function.

The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity.

Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.”

http://www.ncbi.nlm.nih.gov/pubmed/26847930

Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model.

“Many inflammatory mediators, including various cytokines (e.g. interleukins and tumor necrosis factor [TNF]), inflammatory proteases, and histamine are released following mast cell activation.

Endogenous cannabinoids such as palmitoylethanolamide (PEA) and N-arachidonoylethanolamine (anandamide or AEA), were found in peripheral tissues and have been proposed to possess autacoid activity, implying that cannabinoids may downregulate mast cell activation and local inflammation.

Our results indicate that CB1R agonists down-regulate mast cell activation and may be used for relieving inflammatory symptoms mediated by mast cell activation, such as atopic dermatitis, psoriasis, and contact dermatitis.”

http://www.ncbi.nlm.nih.gov/pubmed/26848215

Cannabinoids for the Treatment of Schizophrenia: An Overview.

“Δ9-tetrahydrocannabinol and its analogues are found to have particular application in psychiatry because of their antipsychotic properties suggesting a therapeutic use as neuroleptic agents in limiting psychotic diseases.

These treatments should not only aim to alleviate specific symptoms but also attempt to delay/arrest disease progression.

In the present review, we reported recent studies supporting the view that the cannabinoid signalling system is a key modulatory element in the activity of the striatum and temporal cortex that has been traditionally associated with psychosis and schizophrenia.

This idea is supported by different anatomical, electrophysiological, pharmacological and biochemical data.

Furthermore, these studies indicate that the cannabinoid system is impaired in different psychotic disorders, supporting the idea of developing novel pharmacotherapies with compounds that selectively target specific elements of the cannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/26845552

http://www.thctotalhealthcare.com/category/schizophrenia/

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone-Induced Central Nervous System Demyelination.

“Different types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells.

With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.

The cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro.

Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone-induced demyelination, while 1 mg/kg aggravates the demyelination process.”

http://www.ncbi.nlm.nih.gov/pubmed/26842941

JWH-133, a Selective Cannabinoid CB2 Receptor Agonist, Exerts Toxic Effects on Neuroblastoma SH-SY5Y Cells.

“Endocannabinoid system plays an important role in the regulation of diverse physiological functions.

Although cannabinoid type 2 receptors (CB2) are involved in the modulation of immune system in peripheral tissues, recent findings demonstrated that they are also expressed in the central nervous system and could constitute a new target for the treatment of neurodegenerative disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26842917

Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveal a Mechanism for Regulation of Tumor Progression.

“The G-protein-coupled chemokine receptor, CXCR4, generates signals that lead to cell migration, cell proliferation, and other survival mechanisms which result in the metastatic spread of primary tumor cells to distal organs.

Numerous studies have demonstrated that CXCR4 can form homodimers, or can heterodimerize with other GPCRs to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor.

Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells.

Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2, and ultimately, reduced cancer cell functions such as calcium mobilization and cellular chemotaxis.

Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells, as well as CXCR4-mediated migration of immune cells, it is therefore plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4.

Taken together, the data illustrates a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function, and perhaps, tumor progression.”

http://www.ncbi.nlm.nih.gov/pubmed/26841863

Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain.

“Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system.

Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function.

In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing.

The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far.

It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells.

The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26839718