Monthly Archives: May 2016

Novel role of cannabinoid receptor 2 in inhibiting EGF/EGFR and IGF-I/IGF-IR pathways in breast cancer.

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Image result for Oncotarget.“Breast cancer is the second leading cause of cancer deaths among women.

Cannabinoid receptor 2 (CNR2 or CB2) is an integral part of the endocannabinoid system.

Although CNR2 is highly expressed in the breast cancer tissues as well as breast cancer cell lines, its functional role in breast tumorigenesis is not well understood.

We observed that estrogen receptor-α negative (ERα-) breast cancer cells highly express epidermal growth factor receptor (EGFR) as well as insulin-like growth factor-I receptor (IGF-IR). We also observed IGF-IR upregulation in ERα+ breast cancer cells.

In addition, we found that higher CNR2 expression correlates with better recurrence free survival in ERα- and ERα+ breast cancer patients.

Our studies showed that CNR2 activation inhibited EGF and IGF-I-induced migration and invasion of ERα+ and ERα- breast cancer cells.

In conclusion, we show that CNR2 activation suppresses breast cancer through novel mechanisms by inhibiting EGF/EGFR and IGF-I/IGF-IR signaling axes.”

http://www.ncbi.nlm.nih.gov/pubmed/27213582

Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis

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“Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive.

One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells.

Theoretically, selective CB2 agonists should be devoid of psychoactive effects.

In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis.

The present study suggests that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.

This is the first report of therapeutic effect of a selective CB2 agonist on CIA.

Although the effect was mild, optimization of dosage and/or treatment protocol might enhance the effect.

Perhaps, more potent selective CB2agonists might solve this problem.

Cannabinoids are pharmacologically active components of Cannabis sativa.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243420/

The synthetic cannabinoid WIN55,212-2 mesylate decreases the production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts by activating CB2, TRPV1, TRPA1 and yet unidentified receptor targets

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“Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and cartilage destruction.

In this study we assessed the ability of WIN to modulate cytokine and MMP-3 production in SFs over a wide concentration range and identified specific receptor targets that mediate the effects of this synthetic cannabinoid.

The synthetic cannabinoid WIN in low concentrations exhibits anti-inflammatory effects in synovial fibroblasts independent of CB1 and CB2 while CB2 and yet unidentified receptor targets are responsible for WIN effects in micromolar concentrations.

Our results indicate a TRPV1/TRPA1 dependent mechanism of SF regulation that might be coupled to cellular energy status and calcium content.

In this report we demonstrated anti-inflammatory effects of the synthetic cannabinoid WIN in low and high concentrations.

Furthermore, this study demonstrated anti-inflammatory effects via modulation of TRP channels by WIN. Together, inactivation of TRPs and activation of cannabinoid receptors might also reduce the sensation of pain, which further underlines the potential of WIN in the treatment of chronic inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858820/

Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders.

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“Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases.

Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery.

During past years, cannabinoid CB1 and CB2 receptor ligands from plants or lab were rapidly developed and then various new structures were reported to be cannabinoids.

The CB1 and CB2 receptor ligands offer several therapeutic opportunities for several CNS-related diseases.

Based on the scientific literature, this review provides an overview of CB1 and CB2 receptor synthetic ligands obtained from drug research and in particular those synthesized for therapeutic purposes and potential clinical applications for central nervous system disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/27193072

Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery.

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“Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse.”

http://www.ncbi.nlm.nih.gov/pubmed/27186994

Functional selectivity of CB2 cannabinoid receptor ligands at a canonical and non-canonical pathway.

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“The CB2 cannabinoid receptor remains a tantalizing, but unrealized therapeutic target. CB2 receptor ligands belong to varied structural classes and display extreme functional selectivity. Here we have screened diverse CB2 receptor ligands at canonical (inhibition of adenylyl cyclase) and non-canonical (arrestin recruitment) pathways. The non-classical cannabinoid, CP55940 was the most potent agonist for both pathways, while the classical cannabinoid ligand JWH133 was the most efficacious agonist amongst all the ligands profiled in cyclase assays. In the cyclase assay, other classical cannabinoids showed little (Δ9THC, KM233) to no efficacy (L759633 and L759656). Most aminoalkylindoles including WIN55212-2 were moderate efficacy agonists. The cannabilactone AM1710 was equi-efficacious to CP55940 to inhibit adenylyl cyclase, albeit with lower potency. In the arrestin recruitment assays, all classical cannabinoid ligands failed to recruit arrestins, indicating a bias towards G protein coupling for this class of compound. All aminoalkylindoles tested, except for WIN55212-2 and UR144, failed to recruit arrestin. WIN55212-2 was a low efficacy agonist for arrestin recruitment, while UR144 was arrestin biased with no significant inhibition of cyclase. Endocannabinoids were G protein biased with no arrestin recruitment. The diarylpyrazole antagonist, SR144528 was an inverse agonist in cyclase and arrestin recruitment assays while the aminoalkylindole AM630 and carboxamide JTE907 were inverse agonists in cyclase but low efficacy agonists in arrestin recruitment assays. Thus CB2 receptor ligands display strong and varied functional selectivity at both pathways. Therefore extreme care must be exercised when using these compounds to infer the role of CB2 receptors in vivo.”

http://www.ncbi.nlm.nih.gov/pubmed/27194477

Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.

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“The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC).

Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive.

CONCLUSIONS:

Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.”

http://www.ncbi.nlm.nih.gov/pubmed/27196571

A Central Move for CB2 Receptors.

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“The function of the CB2 cannabinoid receptor in the brain has long been a matter of debate. In this issue of Neuron, Stempel et al. (2016) describe a mechanism whereby endocannabinoid production leads to a cell-intrinsic hyperpolarization that controls self activity.”

http://www.ncbi.nlm.nih.gov/pubmed/27196970

Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent

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“Breast cancer is the leading cause of cancer-related deaths among women aged 34–50 worldwide, and is the most commonly diagnosed metastasizing tumor in women of all ages. Despite advances in understanding breast cancer as a disease, there remains a critical need for novel disease-modifying therapeutics.

Nonspecific cannabinoids, cannabinoid receptor 2 (CB2)-selective, as well as cannabinoid receptor 1 (CB1)-selective compounds have yielded similar antitumor results in several tumor models. The lack of neuronal expression of CB2 receptors precludes CB2 selective compounds from inducing the psychotropic effects that typically accompany CB1 activation.

 Our group and others have shown that CB2 agonists displaying selectivity for the CB2 receptor can decrease tumor cell viability and significantly attenuate cancer-induced bone pain without displaying psychoactive or addictive properties.

…antitumor effects of cannabinoids have been demonstrated in a variety of tumor models…

The antiproliferative effects of a CB2 agonist along with our previous work demonstrating significant efficacy in inhibiting bone cancer pain and slowing bone loss in a murine model of advanced breast cancer strongly suggest that CB2 agonists should be investigated in humans as adjunct therapy for advanced stages of breast cancer.

 Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems.
The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor.
Several groups have shown that both nonselective cannabinoid and CB2-specific compounds decrease breast cancer viability in vitro and in vivo: Δ9-tetrahydrocannabinol and CB2-selective agonist, JWH-133, have been demonstrated to exert considerable antitumoral effects…”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847606/

Does cannabis use moderate smoking cessation outcomes in treatment-seeking tobacco smokers? Analysis from a large multi-center trial.

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“Tobacco and cannabis are frequently used in combination and cannabis co-use may lead to poor tobacco cessation outcomes. Therefore, it is important to explore if cannabis co-use is associated with a reduced likelihood of achieving successful tobacco abstinence among treatment-seeking tobacco smokers.

The present study examined whether current cannabis use moderated tobacco cessation outcomes after 12 weeks of pharmacological treatment with adjunctive behavioral counseling.

 RESULTS:

Controlling for rate of nicotine metabolism, treatment arm, age, sex, alcohol, and level of nicotine dependence, cannabis users were as successful at achieving biochemically verified 7-day point prevalence abstinence compared to tobacco-only smokers.

CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE:

Findings suggest that cannabis use does not hinder the ability to quit tobacco smoking.”

http://www.ncbi.nlm.nih.gov/pubmed/27187893