Tag Archives: endocannabinoid system

Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review).

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“The medicinal properties of extracts from the hemp plant Cannabis sativa have been known for centuries but only in the 90s membrane receptors for the Cannabis major principle were discovered in mammalian cells. Later on the endogenous ligands for the cannabinoid receptors were identified and the term ‘endocannabinoid system’ was coined to indicate the complex signaling system of cannabinoid receptors, endogenous ligands and the enzymes responsible for their biosynthesis and inactivation.

The ‘endocannabinoid system’ is involved in a broad range of functions and in a growing number of pathological conditions.

There is increasing evidence that endocannabinoids are able to inhibit cancer cell growth in culture as well as in animal models.

Most work has focused on the role of endocannabinoids in regulating tumor cell growth and apoptosis and ongoing research is addressed to further dissect the precise mechanisms of cannabinoid antitumor action. However, endocannabinoids are now emerging as suppressors of angiogenesis and tumor spreading since they have been reported to inhibit angiogenesis, cell migration and metastasis in different types of cancer, pointing to a potential role of the endocannabinoid system as a target for a therapeutic approach of such malignant diseases.

The potential use of cannabinoids to retard tumor growth and spreading is even more appealing considering that they show a good safety profile, regarding toxicity, and are already used in cancer patients as palliatives to stimulate appetite and to prevent devastating effects such as nausea, vomiting and pain.”  http://www.ncbi.nlm.nih.gov/pubmed/17342320

https://www.spandidos-publications.com/or/17/4/813

Cannabinoids for Cancer Treatment: Progress and Promise

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“Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy.

 there is overwhelming evidence to suggest that cannabinoids can be explored as chemotherapeutic agents for the treatment of cancer.”

 http://cancerres.aacrjournals.org/content/68/2/339.long

Cannabimimetic fatty acid derivatives in cancer and inflammation.

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“Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca(2+) ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here.”

http://www.ncbi.nlm.nih.gov/pubmed/10785541

The anandamide analog, Met-F-AEA, controls human breast cancer cell migration via the RHOA/RHO kinase signaling pathway.

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“The endocannabinoid system regulates cell proliferation and migration in human breast cancer cells. In this study, we showed that a metabolically stable analog of anandamide, 2-methyl-2′-F-anandamide (Met-F-AEA), inhibited the RHOA activity and caused a RHOA delocalization from the cell membrane to cytosol determining a decrease in actin stress fibers. Overexpression of a dominant negative of RHOA activity and treatment of these cells with a RHO-associated protein kinase (ROCK) inhibitor, Y 27632, mimicked Met-F-AEA effects on actin organization and cell migration. We suggest that the inhibitory effect of Met-F-AEA on tumor cell migration could be related to RHOA-ROCK-dependent signaling pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/18676619

The endocannabinoid system in the cancer therapy: an overview.

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“The endocannabinoid system comprises the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids), and the proteins responsible for their biosynthesis and degradation. This ubiquitous signalling system, that has attracted a great deal of scientist interest in the past 15 years, regulates several physiological and pathological functions. In mammals, among other functions, the endocannabinoid is involved in nervous, cardiovascular, metabolic, reproductive and immune functions. Finally, yet importantly, endocannabinoids are known to exert important antiproliferative actions in a great number of tumor cells including breast, brain, skin, thyroid, prostate and colorectal. The following review describes our current knowledge on the effects of two of the most studied endocannabinoids (AEA and 2-AG) on various types of tumor and summarizes the possible mechanism of observed antitumor effects.”  http://www.ncbi.nlm.nih.gov/pubmed/21428888

http://www.eurekaselect.com/73874/article

Anandamide inhibits adhesion and migration of breast cancer cells.

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“The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB1 receptors could induce a non-invasive phenotype in breast metastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2′-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB1 antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB1 receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB1 receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo.”

http://www.ncbi.nlm.nih.gov/pubmed/16343481

Endocannabinoids in endocrine and related tumours.

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“The ‘endocannabinoid system’, comprising the cannabinoid CB1 and CB2 receptors, their endogenous ligands, endocannabinoids and the enzymes that regulate their biosynthesis and degradation, has drawn a great deal of scientist attention during the last two decades. The endocannabinoid system is involved in a broad range of functions and in a growing number of physiopathological conditions. Indeed, recent evidence indicates that endocannabinoids influence the intracellular events controlling the proliferation of numerous types of endocrine and related cancer cells, thereby leading to both in vitro and in vivo antitumour effects. In particular, they are able to inhibit cell growth, invasion and metastasis of thyroid, breast and prostate tumours. The chief events of endocannabinoids in cancer cell proliferation are reported highlighting the correspondent signalling involved in tumour processes: regulation of adenylyl cyclase, cyclic AMP-protein kinase-A pathway and MEK-extracellular signal-regulated kinase signalling cascade.

Up to date since the isolation and characterisation of the psychoactive component of Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC), about 60 different plant terpeno-phenols more or less related to THC have been isolated and defined cannabinoids. They include cannabidiol (CBD), cannabinol, cannabigerol and cannabichromene. The discovery of these principles stimulated the generation of a whole range of synthetic analogues that included not only compounds structurally similar to phytocannabinoids, but also analogues with different chemical structures, including classic and non-classic cannabinoids and aminoalkylindoles (Howlett et al. 2002) as well as the subsequently discovered endogenous arachidonic acid derivatives or endocannabinoids. The discovery of this family of endogenous cannabinoids (Devane et al. 1992, Mechoulam et al. 1995, Sugiura et al. 1995) has focused much attention on cannabinoids and their pharmacological properties during the last few years (Di Marzo et al. 2004).”

http://erc.endocrinology-journals.org/content/15/2/391.long

The endocannabinoid system and cancer: therapeutic implication

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“The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others).

The main active ingredient of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), produces its effects through activation of CB(1) and CB(2) receptors. CB(1) receptors are expressed at high levels in the central nervous system (CNS), whereas CB(2) receptors are concentrated predominantly, although not exclusively, in cells of the immune system.

Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer.

This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed.

Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients.

Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted.” http://www.ncbi.nlm.nih.gov/pubmed/21410463

“The available literature suggests that the endocannabinoid system may be targeted to suppress the evolution and progression of breast, prostate and bone cancer as well as the accompanying pain syndromes. Many in vitro and in vivo studies have shown that cannabinoids are efficacious in reducing cancer progression (i.e. inhibition of tumour growth and metastases as well as induction of apoptosis and other anti-cancer properties) in breast, prostate and bone cancer. Although this review focuses on these three types of cancer, activation of the endocannabinoid signalling system produces anti-cancer effects in other types of cancer.” http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01327.x/full

Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.

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“It has been proposed that cannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation, and survival in different manners depending on the cell type and its physiopathologic context. However, little is known about the effect of cannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that Delta(9)-tetrahydrocannabinol (THC), through activation of CB(2) cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. In particular, THC arrests cells in G(2)-M via down-regulation of Cdc2, as suggested by the decreased sensitivity to THC acquired by Cdc2-overexpressing cells. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC. We also analyzed by real-time quantitative PCR the expression of CB(1) and CB(2) cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between CB(2) expression and histologic grade of the tumors. There was also an association between CB(2) expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB(2) expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.

Breast cancer is the most common malignant disease among Western women. Although the rates of mortality of breast cancer patients have decreased as a result of early diagnosis by mammograms, certain breast tumors remain reluctant to conventional therapies, and current treatments have side effects that substantially affect the patient’s quality of life. Our findings might set the basis for new strategies for the management of breast cancer.”

http://cancerres.aacrjournals.org/content/66/13/6615.long

Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.

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“Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.”

http://www.ncbi.nlm.nih.gov/pubmed/19887554