Category Archives: Endocannabinoid System

Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect.

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“Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system.

We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors… 

Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells.

Our results collectively suggest that ultraviolet radiation activates paracrine CB(1)-mediated endocannabinoid signaling to negatively regulate melanin synthesis.

The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/21298280

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action.

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“The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated…

CONCLUSIONS:

This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors.

This may contribute to the improvement of long-term palliation or cure of melanoma.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364151/

Cannabidiol Inhibits Growth and Induces Programmed Cell Death in Kaposi Sarcoma–Associated Herpesvirus-Infected Endothelium

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“Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma–associated herpesvirus (KSHV). Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host’s immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed.

Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer.

In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma….

Cannabidiol (CBD) was first isolated in 1940. It is a major component of the plant Cannabis sativa, which is also the source of Δ9-tetrahydrocannabinol (Δ9-THC). Due to its multiple biological activities, CBD has been identified as a potential clinical agent. Moreover, CBD affects these activities without the psychoactive side effects that typify Δ9-THC. Recent studies have documented the potential antitumorigenic properties of CBD in the treatment of various neoplasms, including breast cancer, lung cancer, bladder cancer, glioblastoma,and leukemia.CBD induces these effects through a variety of mechanisms and signaling pathways

CBD has been evaluated clinically for the treatment of various conditions, including anxiety, psychosis, and pain. In contrast to other members of the cannabinoid family, CBD has a strong safety profile and induces no psychotropic effects.Therefore, it has become an attractive agent in the search for new anticancer therapies.Our current study demonstrated that CBD preferentially enhanced apoptosis and inhibited the proliferation of KSHV-infected endothelial cells. This selective targeting of KSHV-induced neoplasia suggests that CBD may have a desirable therapeutic index when used to treat cancer. Moreover, a recent study demonstrated that CBD can be delivered effectively by nasal and transdermal routes, which may be particularly valuable for the treatment of Kaposi sarcoma oral or skin lesions.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527984/

The CB1/CB2 receptor agonist WIN-55,212-2 reduces viability of human Kaposi’s sarcoma cells in vitro.

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“Kaposi’s sarcoma is a highly vascularized mesenchymal neoplasm arising with multiple lesions of the skin. Endogenous cannabinoids have been shown to inhibit proliferation of a wide spectrum of tumor cells. We studied the effects of cannabinoids on human Kaposi’s sarcoma cell proliferation in vitro.

 To do so, we first investigated the presence of the cannabinoid receptors CB(1) and CB(2) mRNAs in the human Kaposi’s sarcoma cell line KS-IMM by RT-PCR and, subsequently, the effects of the mixed CB(1)/CB(2) agonist WIN-55,212-2 (WIN) on cell proliferation in vitro. WIN showed antimitogenic effects on Kaposi’s sarcoma cells…

  In view of the antiproliferative effects of cannabinoids on KS-IMM cells, one could envision the cannabinoid system as a potential target for pharmacological treatment of Kaposi’s sarcoma”

http://www.ncbi.nlm.nih.gov/pubmed/19539619

Cannabinoids for Cancer Treatment: Progress and Promise

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Cancer Research: 68 (2)

“Cannabinoid refers to a group of chemicals naturally found in the marijuana plant Cannabis sativa L. and includes compounds that are either structurally or pharmacologically similar to Δ(9)-tetrahydrocannabinol or those that bind to the cannabinoid receptors. Although anticancer effects of cannabinoids were shown as early as 1975 in Lewis lung carcinoma, renewed interest was generated little after the discovery of the cannabinoid system and cloning of the specific cannabinoid receptors.

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.”

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

Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism.

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“Cannabinoids (CBs) are implicated in the control of cell survival in different types of tumors, but little is known about the role of CB system in pancreatic cancer. Herein, we investigated the in vitro antitumor activity of CBs and the potential role of their receptors in human pancreatic cancer cells MIA PaCa-2…

These findings exclude the involvement of CB receptors in the regulation of MIA PaCa-2 cell growth and put AM251 forward as a candidate for the development of novel compounds worthy to be tested in this type of neoplasia.”

http://www.ncbi.nlm.nih.gov/pubmed/16500647

The role of the pancreatic endocannabinoid system in glucose metabolism.

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“The endogenous cannabinoid system participates in the regulation of energy homeostasis, and this fact led to the identification of a new group of therapeutic agents for complicated obesity and diabetes. Cannabinoid receptor antagonists are now realities in clinical practice. The use of such antagonists for reducing body weight gain, lowering cholesterol and improving glucose homeostasis is based on the ability of the endocannabinoids to coordinately regulate energy homeostasis by interacting with central and peripheral targets, including adipose tissue, muscle, liver and endocrine pancreas. In this review we will analyse the presence of this system in the main cell types of the islets of Langerhans, as well as the physiological relevance of the endocannabinoids and parent acylethanolamides in hormone secretion and glucose homeostasis. We will also analyse the impact that these findings may have in clinical practice and the potential outcome of new therapeutic strategies for modulating glucose homeostasis and insulin/glucagon secretion.”

http://www.ncbi.nlm.nih.gov/pubmed/19285263

Presence of functional cannabinoid receptors in human endocrine pancreas.

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“We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro. We also described the localisation on islet cells of: (1) the endocannabinoid-producing enzymes N-acyl-phosphatidyl ethanolamine-hydrolysing phospholipase D and diacylglycerol lipase; and (2) the endocannabinoid-degrading enzymes fatty acid amidohydrolase and monoacyl glycerol lipase.

RESULTS:

Human islets of Langerhans expressed CB1 and CB2 (also known as CNR1 and CNR2) mRNA and CB1 and CB2 proteins, and also the machinery involved in synthesis and degradation of 2-AG (the most abundant endocannabinoid, levels of which were modulated by glucose). Immunofluorescence revealed that CB1 was densely located in glucagon-secreting alpha cells and less so in insulin-secreting beta cells. CB2 was densely present in somatostatin-secreting delta cells, but absent in alpha and beta cells. In vitro experiments revealed that CB1 stimulation enhanced insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion, showing these cannabinoid receptors to be functional.

CONCLUSIONS/INTERPRETATION:

Together, these results suggest a role for endogenous endocannabinoid signalling in regulation of endocrine secretion in the human pancreas.”

http://www.ncbi.nlm.nih.gov/pubmed/18092149

Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells

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 “Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines …

 Cannabinoids… reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue… results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress–related genes ATF-4 and TRB3.

 These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.

In conclusion, results presented here show that cannabinoids exert a remarkable antitumoral effect on pancreatic cancer cells in vitro and in vivo…

 These findings may help to set the basis for a new therapeutic approach for the treatment of this deadly disease.”

http://www.420magazine.com/forums/pancreatic-cancer/145013-cannabinoids-induce-apoptosis-pancreatic-tumor-cells.html

 

“Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes“

 

Full text: http://cancerres.aacrjournals.org/content/66/13/6748.long

Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia.

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“Cannabinoid CB(1) receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake.

The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic beta-cells.

Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured.

RESULTS:

Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F beta-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F beta-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB(1) receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F beta-cells kept in high glucose.

CONCLUSIONS:

Peripheral endocannabinoid overactivity might explain why CB(1) blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.”

http://jcem.endojournals.org/content/91/8/3171.long