Tag Archives: anti-cancer

Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators.

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“Cannabinoids-endocannaboids are possible preventatives of common diseases including cancers. Cannabinoid receptors (CB(½), TRPV1) are central components of the system. Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways.

Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals.

They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, PPARs, VEGF, NF-κB, p8, CHOP, TRB3 and pro-apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. Paradoxically they are pro-proliferative and anti-apoptotic in some cancers. Differences in receptor expression and concentrations of cannabinoids in cancer and immune cells can elicit anti- or pro-cancer effects through different signal cascades (p38MAPK or PI3/AKT).

Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti-inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways.

Evidence in vivo and in vitro shows EPA and DHA can form endocannabinoids that: (i) are ligands for CB(½) receptors and possibly TRPV-1, (ii) have non-receptor mediated bioactivity, (iii) induce cell cycle arrest, (iii) increase autophagy and apoptosis, and (iv) augment chemotherapeutic actions in vitro. They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on PPARs and NF-kB transcription factors. The use of cannabinoids in cancer treatment is currently limited to chemo- and radio-therapy-associated nausea and cancer-associated pain apart from one trial on brain tumours in patients. Further clinical studies are urgently required to determine the true potential of these intriguing, low toxicity compounds in cancer therapy. Particularly in view of their synergistic effects with chemotherapeutic agents similar to that observed for n-3 LCPUFA.”  https://www.ncbi.nlm.nih.gov/pubmed/23103355

http://www.sciencedirect.com/science/article/pii/S0163782712000537

Therapeutic Potential of Monoacylglycerol Lipase Inhibitors.

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Abstract

 “Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown benefitial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/23142242

A new strategy to block tumor growth by inhibiting endocannabinoid inactivation.

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“Endocannabinoid signaling has been shown to be enhanced in several cancer tissues and malignant cells, and studies in cell lines have shown that this up-regulation might serve the purpose of providing transformed cells with a further means to inhibit their proliferation. Here we investigated the effect of inhibitors of endocannabinoid degradation on the growth of rat thyroid tumor xenografts induced in athymic mice. VDM-11, a selective inhibitor of endocannabinoid cellular re-uptake, and arachidonoyl-serotonin (AA-5-HT), a selective blocker of endocannabinoid enzymatic hydrolysis, both inhibited the growth in vivo of tumor xenografts induced by the subcutaneous injection of rat thyroid transformed (KiMol) cells. This effect was accompanied by significantly enhanced endocannabinoid concentrations in the tumors excised at the end of the in vivo experiments. Endocannabinoids, as well as VDM-11 and AA-5-HT, inhibited the growth in vitro of the transformed rat thyroid cells used to induce the tumors in vivo, and their effect was reversed at least in part by the cannabinoid CB1 receptor antagonist SR141716A. This compound, however, when administered alone, did not enhance, but instead slightly inhibited, the growth of rat thyroid transformed cells both in vitro and in tumor xenografts induced in vivo. These findings indicate that endocannabinoids tonically control tumor growth in vivo by both CB1-mediated and non-CB1-mediated mechanisms and that, irrespective of the molecular mechanism of their anti-proliferative action, inhibitors of their inactivation might be used for the development of novel anti-cancer drugs.”  http://www.ncbi.nlm.nih.gov/pubmed/15289448

“A new strategy to block tumor growth by inhibiting endocannabinoid inactivation”  http://www.fasebj.org/content/early/2004/10/02/fj.04-1754fje.long

50 years of medicinal plant research – every progress in methodology is a progress in science.

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Abstract

“Many scientific methods of analysis have been developed for the investigation of the constituents and biological activities of medicinal plants during the 50 years since the inaugural meeting of the Gesellschaft für Arzneipflanzenforschung (GA). The chromatographic (e. g., TLC, GLC, HPLC), spectroscopic (e. g., UV, IR, 1H- and 13C-NMR, MS), and biological (e. g., anticancer, anti-inflammatory, immunostimulant, antiprotozoal, CNS) techniques utilized for medicinal plant research are briefly reviewed. The contribution that advances in scientific methodology have made to our understanding of the actions of some herbal medicines (e. g., Echinacea, Ginkgo, St John’s wort, Cannabis), as well as to ethnopharmacology and biotechnology, are briefly summarized. Plants have provided many medicinal drugs in the past and remain as a potential source of novel therapeutic agents. Despite all of the powerful analytical techniques available, the majority of plant species has not been investigated chemically or biologically in any great detail and even well known medicinal plants require further clinical study.”

http://www.ncbi.nlm.nih.gov/pubmed/12865964

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

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“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

Cannabinoids: potential anticancer agents.

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Abstract

“Cannabinoids – the active components of Cannabis sativa and their derivatives – exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?”

http://www.ncbi.nlm.nih.gov/pubmed/14570037

 

Marijuana Chemical May Fight Brain Cancer – WebMD

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“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

[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

Possible endocannabinoid control of colorectal cancer growth.

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Abstract

“BACKGROUND & AIMS:

The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit cancer cell proliferation by acting at cannabinoid receptors (CBRs). We studied (1). the levels of endocannabinoids, cannabinoid CB(1) and CB(2) receptors, and fatty acid amide hydrolase (FAAH, which catalyzes endocannabinoid hydrolysis) in colorectal carcinomas (CRC), adenomatous polyps, and neighboring healthy mucosa; and (2). the effects of endocannabinoids, and of inhibitors of their inactivation, on human CRC cell proliferation.

METHODS:

Tissues were obtained from 21 patients by biopsy during colonoscopy. Endocannabinoids were measured by liquid chromatography-mass spectrometry (LC-MS). CB(1), CB(2), and FAAH expression were analyzed by RT-PCR and Western immunoblotting. CRC cell lines (CaCo-2 and DLD-1) were used to test antiproliferative effects.

RESULTS:

All tissues and cells analyzed contain anandamide, 2-AG, CBRs, and FAAH. The levels of the endocannabinoids are 3- and 2-fold higher in adenomas and CRCs than normal mucosa. Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB(1) antagonist SR141716A, but not by the CB(2) antagonist SR144528, and is mimicked by CB(1)-selective, but not CB(2)-selective, agonists. In DLD-1 cells, both CB(1) and CB(2) receptors mediate inhibition of proliferation. Inhibitors of endocannabinoid inactivation enhance CaCo-2 cell endocannabinoid levels and block cell proliferation, this effect being antagonized by SR141716A. CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids.

CONCLUSIONS:

Endocannabinoid levels are enhanced in transformed colon mucosa cells possibly to counteract proliferation via CBRs. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents.”

http://www.ncbi.nlm.nih.gov/pubmed/12949714