Tag Archives: cannabinoid receptors

The endocannabinoid system: a drug discovery perspective.

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Abstract

“The endocannabinoids are lipid messengers that engage the same cell surface receptors targeted by delta9-tetrahydrocannabinol, the active component of marijuana. They are produced by cells in the brain and other tissues and combine with two subtypes of G protein-coupled cannabinoid receptors, CB1 and CB2. Their ability to modulate a variety of pathophysiological processes, including appetite, pain and mood, provides unique opportunities for drug discovery. Three such opportunities are discussed here: reduction of body weight through blockade of CB1 receptors, alleviation of pain through activation of extracerebral cannabinoid receptors, and modulation of pain and anxiety through inhibition of endocannabinoid degradation.”

http://www.ncbi.nlm.nih.gov/pubmed/16044662

[The endocannabinoid system as a target for the development of new drugs for cancer therapy].

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“Studies on the main bioactive components of Cannabis sativa, the cannabinoids, and particularly delta 9-tetrahydrocannabinol (THC), led to the discovery of a new endogenous signalling system that controls several physiological and pathological conditions: the endocannabinoid system. This comprises the cannabinoid receptors, their endogenous agonists–the endocannabinoids–and proteins for endocannabinoid biosynthesis and inactivation.

Recently, evidence has accumulated indicating that stimulation of cannabinoid receptors by either THC or the endocannabinoids influence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to anti-tumour effects both in vitro and in vivo.

This evidence is reviewed here and suggests that future anti-cancer therapy might be developed from our knowledge of how the endocannabinoid system controls the growth and metastasis of malignant cells.”

http://www.ncbi.nlm.nih.gov/pubmed/12723496

Endocannabinoid system modulation in cancer biology and therapy.

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“The discovery of the endocannabinoid system and the recognition of its potential impact in a plethora of pathological conditions, led to the development of therapeutic agents related to either the stimulation or antagonism of CB1 and CB2 cannabinoid receptors, the majority of which are actually tested in preclinical studies for the pharmacotherapy of several diseases. Endocannabinoid-related agents have been reported to affect multiple signaling pathways and biological processes involved in the development of cancer, displaying an interesting anti-proliferative, pro-apoptotic, anti-angiogenic and anti-metastatic activity both in vitro and in vivo in several models of cancer. Emerging evidence suggests that agonists of cannabinoid receptors, which share the useful property to discern between tumor cells and their non-transformed counterparts, could represent novel tumor-selective tools to treat cancer in addition to their already exploited use as palliative drugs to treat chemotherapy-induced nausea, pain and anorexia/weight loss in cancer patients. The aim of this review is to evidence and update the recent emerging knowledge about the role of the endocannabinoid system in cancer biology and the potentiality of its modulation in cancer therapy.”  http://www.ncbi.nlm.nih.gov/pubmed/19559362

http://www.sciencedirect.com/science/article/pii/S1043661809000863

Cannabinoid receptor systems: therapeutic targets for tumour intervention

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Abstract

“The past decade has witnessed a rapid expansion of our understanding of the biological roles of cannabinoids and their cognate receptors. It is now certain that Delta9-tetrahydrocannabinol, the principle psychoactive component of the Cannabis sativa plant, binds and activates membrane receptors of the 7-transmembrane domain, G-protein-coupled superfamily. Several putative endocannabinoids have since been identified, including anandamide, 2-arachidonyl glycerol and noladin ether. Synthesis of numerous cannabinomimetics has also greatly expanded the repertoire of cannabinoid receptor ligands with the pharmacodynamic properties of agonists, antagonists and inverse agonists. Collectively, these ligands have proven to be powerful tools both for the molecular characterisation of cannabinoid receptors and the delineation of their intrinsic signalling pathways. Much of our understanding of the signalling mechanisms activated by cannabinoids is derived from studies of receptors expressed by tumour cells; hence, this review provides a succinct summary of the molecular pharmacology of cannabinoid receptors and their roles in tumour cell biology. Moreover, there is now a genuine expectation that the manipulation of cannabinoid receptor systems may have therapeutic potential for a diverse range of human diseases. Thus, this review also summarises the demonstrated antitumour actions of cannabinoids and indicates possible avenues for the future development of cannabinoids as antitumour agents.”

http://www.ncbi.nlm.nih.gov/pubmed/14640910

Changes in the Endocannabinoid System May Give Insight into new and Effective Treatments for Cancer

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“The endocannabinoid system comprises specific cannabinoid receptors such as Cb1 and Cb2, the endogenous ligands (anandamide and 2-arachidonyl glycerol among others) and the proteins responsible for their synthesis and degradation. This system has become the focus of research in recent years because of its potential therapeutic value several disease states. The following review describes our current knowledge of the changes that occur in the endocannabinoid system during carcinogenesis and then focuses on the effects of anandamide on various aspects of the carcinogenic process such as growth, migration, and angiogenesis in tumors from various origins.

Marijuana and its derivatives have been used in medicine for centuries, however, it was not until the isolation of the psychoactive component of Cannabis sativa (Δ9-tetrahydrocannabinol; Δ9-THC) and the subsequent discovery of the endogenous cannabinoid signaling system that research into the therapeutic value of this system reemerged. Ongoing research is determining that regulation of the endocannabinoid system may be effective in the treatment of pain (Calignano et al., 1998; Manzanares et al., 1999), glaucoma (Voth and Schwartz, 1997), and neurodegenerative disorders such as Parkinson’s disease (Piomelli et al., 2000) and multiple sclerosis (Baker et al., 2000). In addition, cannabinoids might be effective anti-tumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture (De Petrocellis et al., 1998; Ruiz et al., 1999; Sanchez et al., 1998, 2001) and in laboratory animals (Galve-Roperh et al., 2000).

In conclusion, the endocannabinoid system exerts a myriad of effects on tumor cell growth, progression, angiogenesis, and migration. With a notable few exceptions, targeting the endocannabinoid system with agents that activate cannabinoid receptors or increase the endogenous levels of AEA may prove to have therapeutic benefit in the treatment of various cancers. Further studies into the downstream consequences of AEA treatment are required and may illuminate other potential therapeutic targets.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791688/

Marijuana takes on colon cancer

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“The chemicals in marijuana could put the brakes on colon cancer, according to new research. That doesn’t mean smoking a joint will help, though, as the chemicals only form part of the process.

Raymond DuBois and colleagues at the University of Texas in Houston discovered that a key receptor for cannabinoids, which are found in marijuana, is turned off in most types of human colon cancer.

Without this receptor, a protein called survivin, which stops cells from dying, increases unchecked and causes tumour growth.

To better understand the role that the receptor, called CB1, plays in cancer progression, the researchers manipulated its expression in mice that had been genetically engineered to spontaneously develop colon tumours.

“When we knocked out the receptor, the number of tumors went up dramatically,” says DuBois. Alternatively, when mice with normal CB1 receptors were treated with a cannabinoid compound, their tumours shrank.

Dual attack

The findings suggest a two-step treatment plan for colon cancer, as well as for other cancers that might be linked to this receptor.

First, turn the CB1 receptor back on, and then activate it with drugs currently in development that mimic marijuana. But how to turn it on?

The researchers found that in human colon cancer cells, the gene that makes the receptor is blocked by a process called methylation, in which a small chemical group is added to the DNA.

Treating the cells with decitibine – a demethylating drug already approved for use in humans – removed the chemical group and the gene began making the receptor. Drugs that mimic marijuana might then activate the receptor, although DuBois did not test this.”

 

http://www.newscientist.com/article/dn14451-marijuana-takes-on-colon-cancer.html

Cannabinoids and the digestive tract.

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“In the digestive tract there is evidence for the presence of high levels of endocannabinoids (anandamide and 2-arachidonoylglycerol) and enzymes involved in the synthesis and metabolism of endocannabinoids. Immunohistochemical studies have shown the presence of CB1 receptors on myenteric and submucosal nerve plexuses along the alimentary tract. Pharmacological studies have shown that activation of CB1 receptors produces relaxation of the lower oesophageal sphincter, inhibition of gastric motility and acid secretion, as well as intestinal motility and secretion. In general, CB1-induced inhibition of intestinal motility and secretion is due to reduced acetylcholine release from enteric nerves. Conversely, endocannabinoids stimulate intestinal primary sensory neurons via the vanilloid VR1 receptor, resulting in enteritis and enhanced motility. The endogenous cannabinoid system has been found to be involved in the physiological control of colonic motility and in some pathophysiological states, including paralytic ileus, intestinal inflammation and cholera toxin-induced diarrhoea. Cannabinoids also possess antiemetic effects mediated by activation of central and peripheral CB1 receptors.

Pharmacological modulation of the endogenous cannabinoid system could provide a new therapeutic target for the treatment of a number of gastrointestinal diseases, including nausea and vomiting, gastric ulcers, secretory diarrhoea, paralytic ileus, inflammatory bowel disease, colon cancer and gastro-oesophageal reflux conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/16596788

Alternative targets within the endocannabinoid system for future treatment of gastrointestinal diseases.

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Abstract

“Many beneficial effects of herbal and synthetic cannabinoids on gut motility and inflammation have been demonstrated, suggesting a vast potential for these compounds in the treatment of gastrointestinal disorders. These effects are based on the so-called ‘endocannabinoid system’ (ECS), a cooperating network of molecules that regulate the metabolism of the body’s own and of exogenously administered cannabinoids. The ECS in the gastrointestinal tract quickly responds to homeostatic disturbances by de novo synthesis of its components to maintain homeostasis, thereby offering many potential targets for pharmacological intervention. Of major therapeutic interest are nonpsychoactive cannabinoids or compounds that do not directly target cannabinoid receptors but still possess cannabinoid-like properties. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids are becoming increasingly promising alternative therapeutic tools to manipulate the ECS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174079/

Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent.

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Abstract

“AIM:

We hypothesized that the anticancer activity of cannabinoids was linked to induction of phosphatases.

MATERIALS AND METHODS:

The effects of cannabidiol (CBD) and the synthetic cannabinoid WIN-55,212 (WIN) on LNCaP (prostate) and SW480 (colon) cancer cell proliferation were determined by cell counting; apoptosis was determined by cleavage of poly(ADP)ribose polymerase (PARP) and caspase-3 (Western blots); and phosphatase mRNAs were determined by real-time PCR. The role of phosphatases and cannabinoid receptors in mediating CBD- and WIN-induced apoptosis was determined by inhibition and receptor knockdown.

RESULTS:

CBD and WIN inhibited LNCaP and SW480 cell growth and induced mRNA expression of several phosphatases, and the phosphatase inhibitor sodium orthovanadate significantly inhibited cannabinoid-induced PARP cleavage in both cell lines, whereas only CBD-induced apoptosis was CB1 and CB2 receptor-dependent.

CONCLUSION:

Cannabinoid receptor agonists induce phosphatases and phosphatase-dependent apoptosis in cancer cell lines; however, the role of the CB receptor in mediating this response is ligand-dependent.”

http://www.ncbi.nlm.nih.gov/pubmed/22110202

Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing.

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Abstract

“BACKGROUND & AIMS:

Two G-protein-coupled cannabinoid receptors, termed CB1 and CB2, have been identified and several mammalian enteric nervous systems express CB1 receptors and produce endocannabinoids. An immunomodulatory role for the endocannabinoid system in gastrointestinal inflammatory disorders has been proposed and this study sought to determine the location of both cannabinoid receptors in human colon and to investigate epithelial receptor function.

METHODS:

The location of CB1 and CB2 receptors in human colonic tissue was determined by immunohistochemistry. Primary colonic epithelial cells were treated with both synthetic and endogenous cannabinoids in vitro, and biochemical coupling of the receptors to known signaling events was determined by immunoblotting. Human colonic epithelial cell lines were used in cannabinoid-binding studies and as a model for in vitro wound-healing experiments.

RESULTS:

CB1-receptor immunoreactivity was evident in normal colonic epithelium, smooth muscle, and the submucosal myenteric plexus. CB1- and CB2-receptor expression was present on plasma cells in the lamina propria, whereas only CB2 was present on macrophages. CB2 immunoreactivity was seen in the epithelium of colonic tissue characteristic of inflammatory bowel disease. Cannabinoids enhanced epithelial wound closure either alone or in combination with lysophosphatidic acid through a CB1-lysophosphatidic acid 1 heteromeric receptor complex.

CONCLUSIONS:

CB1 receptors are expressed in normal human colon and colonic epithelium is responsive biochemically and functionally to cannabinoids. Increased epithelial CB2-receptor expression in human inflammatory bowel disease tissue implies an immunomodulatory role that may impact on mucosal immunity.”

http://www.ncbi.nlm.nih.gov/pubmed/16083701