Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor

Posted on July 13, 2015 by David

“We have previously shown that AEA exerts growth-suppressing effects on cholangiocarcinoma by inducing apoptosis.

At the time, we assumed that AEA was acting via a receptor-independent mechanism.

However, given the recent discovery and characterization of GPR55 as a novel AEA receptor, our data need to be reassessed to determine if GPR55 activation can decrease cholangiocarcinoma cell proliferation.

Thus, our aims are to determine if these AEA-mediated effects on cholangiocarcinoma cell growth can be attributed to the activation of GPR55.

This data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma.

In conclusion, we have clearly demonstrated a role for GPR55 in the antiproliferative effects of AEA in vivo andin vitro…

Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies that target GPR55 may prove beneficial for the treatment of this devastating disease.

Consistent with our observation that AEA has antiproliferative and pro-apoptotic properties, cannabinoids of various origins (endogenous, plant-derived or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126905/

The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway.

Posted on July 13, 2015 by David

“Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options.

Marijuana and its derivatives have been used in medicine for many centuries.

…cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Indeed, we have recently demonstrated that the endocannabinoid anandamide (AEA) has antiproliferative effects on cholangiocarcinoma cell lines in vitro via a cannabinoid receptor-independent pathway involving the stabilization of lipid raft-membrane structures and the recruitment of death-receptor complexes into the lipid rafts.

Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment.

The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA, would prove beneficial for the treatment of this devastating disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604798/

Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

Posted on July 13, 2015 by David

“Cholangiocarcinomas are devastating cancers of intrahepatic and extrahepatic origin that are increasing in both their worldwide incidence and mortality rates.

Conventional chemotherapy and radiation therapy are not effective in prolonging long-term survival; therefore it is important to understand the cellular mechanisms of cholangiocarcinoma cell growth with a view to develop novel chemopreventive strategies.

We have recently demonstrated that the endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) exert opposing effects on cholangiocarcinoma cell growth in vitro via cannabinoid receptor-independent mechanisms.

AEA increased presenilin 1 expression and recruitment into the γ-secretase complex whereas 2-AG increased expression and recruitment of presenilin 2.

The development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for the treatment of this devastating disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872061/

Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts.

Posted on July 13, 2015 by David

The Journal of Biological Chemistry

“Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options…

Marijuana and its derivatives have been used in medicine for many centuries, and presently there is an emerging renaissance in the study of the therapeutic effects of cannabinoids…

In addition, cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines…

These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.

Consistent with our observation that AEA has antiproliferative and proapoptotic properties, cannabinoids of various origins (endogenous, plant-derived, or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.

In conclusion, we have clearly demonstrated opposing actions of the endocannabinoids AEA and 2-AG on cholangiocarcinoma cell proliferation and have shown that these actions are via a cannabinoid receptor-independent but lipid raft-mediated pathway. Furthermore we have shown that the antiproliferative/proapoptotic actions of AEA are mediated via an accumulation of ceramide and the recruitment of the Fas death receptor into the lipid rafts. Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA would prove beneficial for the treatment of this devastating disease.”

http://www.jbc.org/content/282/17/13098.long

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

Posted on July 11, 2015 by David

“Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia.

In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases.

In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor.”

http://www.ncbi.nlm.nih.gov/pubmed/26152606

Endocannabinoid signaling in female reproductive events: a potential therapeutic target?

Posted on July 1, 2015 by David

“Nearly 30 years after the discovery in 1964 of the psychoactive ingredient of cannabis (Cannabis sativa), Δ9-tetrahydrocannabinol, its endogenous counterparts were discovered and collectively termed endocannabinoids (eCBs): N-arachidonoylethanolamine (anandamide) in 1992 and 2-arachidonoylglycerol in 1995.

Since then, intense research has identified additional eCBs and an ensemble of proteins that bind, synthesize and degrade them, the so-called eCB system.

Altogether, these new compounds have been recognized as key mediators of several aspects of human pathophysiology, and in particular of female fertility.

Here, the main features of the eCB system are presented, in order to put in a better perspective the relevance of eCB signaling in virtually all steps of human reproduction and to highlight emerging hopes that elements of this system might indeed become novel targets to combat fertility problems.”

http://www.ncbi.nlm.nih.gov/pubmed/26126134

Roles for the endocannabinoid system in ethanol-motivated behavior.

Posted on July 1, 2015 by David

“Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed.

The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system.

For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways.

Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients.

In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior.

Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination.”

http://www.ncbi.nlm.nih.gov/pubmed/26123153

Δ-9 Tetrahydrocannabinol inhibits growth and metastasis of lung cancer.

Posted on June 29, 2015 by David

Image result for harvard university logo

“Lung cancer is the major cause of cancer-related mortality worldwide.

Many of these over-express epidermal growth factor receptor (EGFR), and are usually highly aggressive and resistant to chemotherapy.

Recent studies have shown that Δ-9 Tetrahydrocannabinol (THC), the major component of Cannabis sativa, possess anti-tumor properties against various types of cancers.

However, not much is known about its effect on lung cancer. In this study, we sought to characterize the effect of THC on EGF-induced growth and metastasis of human non small lung cancer cell (NSCLC) lines A549 and SW-1573.

We demonstrate that these cell lines and primary tumor samples derived from lung cancer patients express cannabinoids receptors CB₁ and CB₂, the known targets for THC action.

We further show that THC inhibits EGF-induced growth in these cell lines.

In addition THC attenuated EGF-stimulated chemotaxis and chemoinvasion.

Next we characterized the effect of THC on in vivo lung cancer growth and metastasis in a murine model. A549 cells were implanted in SCID mice (n=6 per group) through subcutaneous and intravenous injections to generate subcutaneous and lung metastatic cancer, respectively. THC (5mg/kg body wt.) was administered once daily through intraperitoneal injections for 21 days. The mice were analyzed for tumor growth and lung metastasis.

A significant reduction (~50%) in tumor weight and volume were observed in THC treated animals compared to the vehicle treated animals.

THC treated animals also showed a significant (~60%) reduction in macroscopic lesions on the lung surface in comparison to vehicle treated control.

Immunohistochemical analysis of the tumor samples from THC treated animals revealed anti-proliferative and anti-angiogenic effects of THC with significant reduction in staining for Ki67, a proliferative marker and CD31, an endothelial marker indicative of vascularization. Investigation into the signaling events associated with reduced EGF-induced functional effects revealed that THC also inhibits EGF-induced Akt phosphorylation. Akt is a central signaling molecule of EGFR-mediated signaling pathways and it regulates a diverse array of cellular functions, including proliferation, angiogenesis, invasion and apoptosis.

Cumulatively, these studies indicate that THC has anti-tumorigenic and anti-metastatic effects against lung cancer. Novel therapies against EGFR overexpressing, aggressive and chemotherapy resistant lung cancers may include targeting the cannabinoids receptors.”

http://cancerres.aacrjournals.org/content/67/9_Supplement/4749.short

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

Biomedical benefits of cannabinoids?

Posted on June 24, 2015 by David

“Cannabinoids appear to be of therapeutic value as antiemetics, antispasmodics, analgesics and appetite stimulants and may have potential uses in epilepsy, glaucoma and asthma.

This paper reviews the clinical trials which have been carried out with cannabinoids including Δ⁹-tetrahydrocannabinol (THC) and synthetic cannabinoids such as nabilone and levonantradol, and discusses the advantages and adverse effects of cannabinoids in clinical use.

The place of cannabinoids in modern medicine remains to be properly evaluated, but present evidence suggests that they could be valuable, particularly as adjuvants, for symptom control in a range of conditions for which standard drugs are not fully satisfactory.”

http://www.ncbi.nlm.nih.gov/pubmed/20575778

Activation of cannabinoid receptors prevents antigen-induced asthma-like reaction in guinea pigs.

Posted on June 24, 2015 by David

“In this study we evaluated the effects of the CB1/CB2 cannabinoid receptor agonist on antigen-induced asthma-like reaction in sensitized guinea pigs…

These findings suggest that targeting cannabinoid receptors could be a novel preventative therapeutic strategy in asthmatic patients.”

http://www.ncbi.nlm.nih.gov/pubmed/18266975