Update on the endocannabinoid system as an anticancer target.

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“INTRODUCTION:

Recent studies have shown that the endocannabinoid system (ECS) could offer an attractive antitumor target. Numerous findings suggest the involvement of this system (constituted mainly by cannabinoid receptors, endogenous compounds and the enzymes for their synthesis and degradation) in cancer cell growth in vitro and in vivo.

AREAS COVERED:

This review covers literature from the past decade which highlights the potential of targeting the ECS for cancer treatment. In particular, the levels of endocannabinoids and the expression of their receptors in several types of cancer are discussed, along with the signaling pathways involved in the endocannabinoid antitumor effects. Furthermore, the beneficial and adverse effects of old and novel compounds in clinical use are discussed.

EXPERT OPINION:

One direction that should be pursued in antitumor therapy is to select compounds with reduced psychoactivity. This is known to be connected to the CB1 receptor; thus, targeting the CB2 receptor is a popular objective. CB1 receptors could be maintained as a target to design new compounds, and mixed CB1-CB2 ligands could be effective if they are able to not cross the BBB. Furthermore, targeting the ECS with agents that activate cannabinoid receptors or inhibitors of endogenous degrading systems such as fatty acid amide hydrolase inhibitors may have relevant therapeutic impact on tumor growth. Additional studies into the downstream consequences of endocannabinoid treatment are required and may illuminate other potential therapeutic targets.”  http://www.ncbi.nlm.nih.gov/pubmed/21244344

“Update on the endocannabinoid system as an anticancer target”  http://www.tandfonline.com/doi/abs/10.1517/14728222.2011.553606?journalCode=iett20

Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents.

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“Cannabinoids (the active components of Cannabis sativa) and their derivatives have received renewed interest in recent years due to their diverse pharmacological activities. In particular, cannabinoids offer potential applications as anti-tumour drugs, based on the ability of some members of this class of compounds to limit cell proliferation and to induce tumour-selective cell death. Although synthetic cannabinoids may have pro-tumour effects in vivo due to their immunosuppressive properties, predominantly inhibitory effects on tumour growth and migration, angiogenesis, metastasis, and also inflammation have been described. Emerging evidence suggests that agonists of cannabinoid receptors expressed by tumour cells may offer a novel strategy to treat cancer. In this chapter we review the more recent results generating interest in the field of cannabinoids and cancer, and provide novel suggestions for the development, exploration and use of cannabinoid agonists for cancer therapy, not only as palliative but also as curative drugs.” https://www.ncbi.nlm.nih.gov/pubmed/19285265

“Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents” http://www.bprcem.com/article/S1521-690X(09)00005-0/abstract

Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids.

“Cannabinoids, the active components of the cannabis plant, have some clinical merit both as an anti-emetic and appetite stimulant in cachexic patients. Recently, interest in developing cannabinoids as therapies has increased following reports that they possess anti-tumour properties.

 Research into cannabinoids as anti-cancer agents is in its infancy, and has mainly focussed on the pro-apoptotic effects of this class of agent. Impressive anti-cancer activities have been reported; actions that are mediated in large part by disruptions to ubiquitous signalling pathways such as ERK and PI3-K. However, recent developments have highlighted a putative role for cannabinoids as anti-inflammatory agents. Chronic inflammation has been associated with neoplasia for sometime, and as a consequence, reducing inflammation as a way of impacting cancer presents a new role for these compounds.

 This article reviews the ever-changing relationship between cannabinoids and cancer, and updates our understanding of this class of agent. Furthermore, the relationship between chronic inflammation and cancer, and how cannabinoids can impact this relationship will be described.”

http://www.ncbi.nlm.nih.gov/pubmed/20925645

Cannabinoid receptor ligands as potential anticancer agents–high hopes for new therapies?

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“OBJECTIVES:

The endocannabinoid system is an endogenous lipid signalling network comprising arachidonic-acid-derived ligands, cannabinoid (CB) receptors, transporters and endocannabinoid degrading enzymes. The CB(1) receptor is predominantly expressed in neurons but is also co-expressed with the CB(2) receptor in peripheral tissues. In recent years, CB receptor ligands, including Delta(9)-tetrahydrocannabinol, have been proposed as potential anticancer agents.

KEY FINDINGS:

This review critically discusses the pharmacology of CB receptor activation as a novel therapeutic anticancer strategy in terms of ligand selectivity, tissue specificity and potency. Intriguingly, antitumour effects mediated by cannabinoids are not confined to inhibition of cancer cell proliferation; cannabinoids also reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and attenuate inflammatory processes. In the last decade several new selective CB(1) and CB(2) receptor agents have been described, but most studies in the area of cancer research have used non-selective CB ligands. Moreover, many of these ligands exert prominent CB receptor-independent pharmacological effects, such as activation of the G-protein-coupled receptor GPR55, peroxisome proliferator-activated receptor gamma and the transient receptor potential vanilloid channels.

SUMMARY:

The role of the endocannabinoid system in tumourigenesis is still poorly understood and the molecular mechanisms of cannabinoid anticancer action need to be elucidated. The development of CB(2)-selective anticancer agents could be advantageous in light of the unwanted central effects exerted by CB(1) receptor ligands. Probably the most interesting question is whether cannabinoids could be useful in chemoprevention or in combination with established chemotherapeutic agents.”

http://www.ncbi.nlm.nih.gov/pubmed/19589225

Scientists believe marijuana compound could fight cancer

“Scientists in California believe they may have discovered a compound in marijuana that can reduce the aggressiveness of some forms of cancer.

The San Francisco Gate reports on the data that has been years in the making. While marijuana has been shown to help reduce nausea and pain in cancer patients, scientists believe that a compound in marijuana has the ability to “turn off” the activity of a gene responsible for metastasis in breast and other types of cancers.

The research team is working out of San Francisco’s California Pacific Medical Center Research Institute and have been working for years on the study. The compound they’re focused on, called cannabidiol, does not produce the psychotropic high associated with marijuana.

Last year, the team published a small study showing the positive effects of cannabidiol on mice. New data is about to be released that expands upon the previous results that the researchers hope will help propel the study even further.

“The preclinical trial data is very strong, and there’s no toxicity. There’s really a lot of research to move ahead with and to get people excited,” said Sean McAllister, who is working alongside scientist Pierre Desprez in the study.

Desprez and McAllister believe that their merging of separate areas of study was serendipitous.

Desprez had been studying the protein ID-1, which he found to play an important role in how cancer could spread. McAllister, on the other hand, was focused on studying anabolic steroids in drug abuse. He soon became focused on with the role non-psychotropic cannabidiol, or CBD, interacts with cancer.

McAllister, after hearing an internal seminar from Desprez on his studies of ID-1, came up with the question “How effective would cannabidiol be on targeting metastatic cancer cells?”

The two then teamed up, with Desprez armed with ID-1 cancer-causing protein, and McAllister with CBD, his cancer-fighting compound.

For their experimentation, the doctors exposed ID-1 to CBD in a petri dish. In a shocking result, the ID-1, the cancer-causing protein, reverted to a normal state and stopped acting “crazy.”

“We thought we did the experiment the wrong way,” McAllister said of the overwhelming results.

However, their results proved to be consisted.

“I told Sean, ‘Maybe your drug is working through my gene,’ ” Desprez said.

What the researchers have discovered thus far in their research is that CBD turns off the overexpression of ID-1, which prevents it from traveling to foreign tissues. Thus, the metastasization – cancer’s fatal ability – is blocked.

In the wake of their positive results, the doctors were forced to emphasize that the CBD will only work in the presence of high levels of ID-1 and these do not include all cancerous tumors but, rather, aggressive, metastatic cells. High levels have been found in leukemia, colorectal, pancreatic, lung, ovarian, brain and other cancers.”
Read more: http://www.irishcentral.com/news/Scientists-believe-marijuana-compound-could-fight-cancer-170689736.html#ixzz29rQbc2oS

Marijuana Chemical May Fight Brain Cancer – WebMD

“Active Component In Marijuana Targets Aggressive Brain Cancer Cells, Study Says
 
The active chemical in marijuana promotes the death of brain cancer cells by essentially helping them feed upon themselves, researchers in Spain report.Guillermo Velasco and colleagues at Complutense University in Spain have found that the active ingredient in marijuana, THC, causes brain cancer cells to undergo a process called autophagy. Autophagy is the breakdown of a cell that occurs when the cell essentially self-digests.The team discovered that cannabinoids such as THC had anticancer effects in mice with human brain cancer cells and people with brain tumors. When mice with the human brain cancer cells received the THC, the tumor growth shrank.Two patients enrolled in a clinical trial received THC directly to the brain as an experimental treatment for recurrent glioblastoma multiforme, a highly aggressive brain tumor.  Biopsies taken before and after treatment helped track their progress.  After receiving the THC, there was evidence of increased autophagy activity.

The findings appear in the April 1 issue of the Journal of Clinical Investigation.

The patients did not have any toxic effects from the treatment. Previous studies of THC for the treatment of cancer have also found the therapy to be well tolerated, according to background information in journal article.

Study authors say their findings could lead to new strategies for preventing tumor growth.”

http://www.webmd.com/cancer/brain-cancer/news/20090401/marijuana-chemical-may-fight-brain-cancer

“Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells”: http://www.jci.org/articles/view/37948

Marijuana Compounds Could Beat Back Brain Cancer – ABCNews

“Preliminary research suggests that a combination of compounds in marijuana could help fight off a particularly deadly form of brain cancer.

But the findings shouldn’t send patients rushing to buy pot: the levels used in the research appear to be too high to obtain through smoking. And there’s no sign yet that the approach works in laboratory animals, let alone people.

Still, the finding does suggest that more than one compound in marijuana might boost cancer treatment, said study author Sean McAllister, an associate scientist at California Pacific Medical Center Research Institute in San Francisco. “Combination therapies might be more appropriate,” McAllister said.

Researchers have long studied the compounds in marijuana known as cannabinoids, which are thought to hold possible health benefits. One, known as THC, is well known for its role in making people high when they smoke or eat pot. Researchers have been testing it as a treatment for the brain tumors known as glioblastomas.

In the new study, researchers tested THC and cannabidiol, another compound from marijuana, on brain cancer cells. The findings appear in the January issue of Molecular Cancer Therapeutics.

The study authors found that the combination treatment seemed to work better at killing the cancerous cells and preventing them from growing back.

About 9,000 people in the United States develop glioblastomas each year, said Dr. Paul Graham Fisher, chief of the Division of Child Neurology at Stanford University and Lucile Packard Children’s Hospital. The most famous patient was the late U.S. Senator Ted Kennedy.

The prognosis for people with the condition is grim because tumors spread throughout the brain. It can be impossible for treatments to remove the entire tumor, Fisher said.

“No matter what you do, this tumor has a larger border than you ever think,” he said. “We know there are microscopic satellites all throughout one side of the brain and pretty soon in the other side of the brain. The only thing that will fix this disease is something that provides a more blanket approach.”

Instead of targeting the tumors itself, he explained, treatments need to do something like disrupt the pathways that cancer cells use to communicate.

In the big picture, “you’re seeing a lot more thinking outside the box about trying to treat glioblastoma,” he said. “I think in the next 10 to 15 years we’re going to start seeing progress forward.”

For now, he said, there’s no evidence that marijuana is good or bad for glioblastoma tumors.

Back in the laboratory, McAllister said the next step is to test the combination treatment on laboratory animals and then on people. The treatment may be given to people directly through the brain, which could be expensive. But the compounds themselves may not be expensive, McAllister said.

As for the idea of getting the same effect through a couple of marijuana joints, he had this to say: “It’s unlikely that you could reach effective concentrations by smoking the plant.””

http://abcnews.go.com/Health/Healthday/marijuana-compounds-beat-back-brain-cancer/story?id=9534388

“Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells.”
http://www.ncbi.nlm.nih.gov/pubmed/16078104

The Endocannabinoid System and the Brain.

Abstract

“The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.”

http://www.ncbi.nlm.nih.gov/pubmed/22804774

[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