cannabinoids and cancer / Agosto 2016

Endocannabinoid system as a regulator of tumor cell malignancy - biological pathways and clinical significance.

Pyszniak M(1), Tabarkiewicz J(2), Łuszczki JJ(3).

Author information:

(1)Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine; Department of Immunology, Faculty of Medicine, University of Rzeszów, Rzeszów; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warszawa.

(2)Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine; Department of Immunology, Faculty of Medicine, University of Rzeszów, Rzeszów. (3)Department of Pathophysiology, Medical University of Lublin; Isobolographic Analysis Laboratory, Institute of Agricultural Medicine, Lublin, Poland.

The endocannabinoid system (ECS) comprises cannabinoid receptors (CBs), endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endo)cannabinoids. To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB. Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome. Although most effects of (endo)cannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules. It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared. This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology. We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival. A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy.

In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol- 5-yl)methyl]-piperidin-1-yl}( 1H-1,2,4-triazol-1-yl)m ethanone (JJKK-048).

 Aaltonen N(1), Kedzierska E(2), Orzelska-Gorka J(2), Lehtonen M(3), Navia-Paldanius D(3), Jakupovic H(3), Savinainen J(3), Nevalainen T(3), Laitinen JT(3), Parkkari T(3), Gynther M(3).

Author information:

(1)University of Eastern Finland; Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

(2)Medical University of Lublin.

(3)University of Eastern Finland;

Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as primary source fo neuroinflammatory prostaglandin synthesis in brain. MAGL activity also contributes in cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders as well as cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol- 5-yl)methyl]-piperidin-1-yl}( 1H-1,2,4-triazol-1-yl)m ethanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here we characterize in vivo effects of JJKK-048.

Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling (ABPP) revealed that JJKK-048 maintains good selectivity towards MAGL over other serine hydrolases. Our results also showed for the first time that JJKK-048 promoted significant analgesia in writhing test with the low dose that did not cause cannabimimetic side effects. A high dose of JJKK-048 induced analgesia both in writhing test and in tail immersion test, as well as hypomotility and hypothermia but
 not catalepsy.

The American Society for Pharmacology and Experimental Therapeutics.

Discovery of novel Tetrahydrobenzo[b]thiophene and pyrrole based scaffolds as potent and selective CB2 receptor ligands: The structural elements controlling binding affinity, selectivity and functionality.

Osman NA(1), Ligresti A(2), Klein CD(3), Allarà M(2), Rabbito A(2), Di Marzo V(2), Abouzid KA(4), Abadi AH(1).

Author information:

(1)Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt. 

(2)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.

(3)Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.

(4)Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo.. eg.

CB2-based therapeutics show strong potential in the treatment of diverse diseases such as inflammation, multiple sclerosis, pain, immune-related disorders, osteoporosis and cancer, without eliciting the typical neurobehavioral side effects of CB1 ligands. For this reason, research activities are currently directed towards the development of CB2 selective ligands. Herein, the synthesis of novel heterocyclic-based CB2 selective compounds is reported.

A set of 2,5-dialkyl-1-phenyl-1H- pyrrole-3-carboxamides, 5-subtituted-2-(acylamino)/(2- sulphonylamino)-thiophene-3- carboxylates and 2-(acylamino)/(2- sulphonylamino)- tetrahydrobenzo[b]thiophene-3- carboxylates were synthesized. Biological results revealed compounds with remarkably high CB2 binding affinity and CB2/CB1 subtype selectivity. Compound 19a and 19b from the pyrrole series exhibited the highest CB2 receptor affinity (Ki = 7.59 and 6.15 nM, respectively), as well as the highest CB2/CB1 subtype selectivity (∼70 and ∼200-fold, respectively). In addition, compound 6b from the tetrahydrobenzo[b]thiophene series presented the most potent and selective CB2 ligand in this series (Ki = 2.15 nM and CB2 subtype selectivity of almost 500-fold over CB1). Compound 6b showed a full agonism, while compounds 19a and 19b acted as inverse agonists when tested in an adenylate cyclase assay.

The present findings thus pave the way to the design and optimization of heterocyclic-based scaffolds with lipophilic carboxamide and/or retroamide substituent that can be exploited as potential CB2 receptor activity modulators.

Copyright © 2016 Elsevier Masson SAS. All rights reserved.


Cannabinoids for Symptom Management and Cancer Therapy: The Evidence. 

Davis MP(1).


Author information:

(1)From Cleveland Clinic Lerner School of Medicine, Case Western University, and Palliative Medicine and Supportive Oncology Services, Division of Solid Tumor, Taussig Cancer Institute, The Cleveland Clinic, Cleveland, Ohio.

Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. 

Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity.

There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard.

Copyright © 2016 by the National Comprehensive Cancer Network.

5. Development.
 Cannabinoid receptor signaling regulates liver development and metabolism.
Liu LY(1), Alexa K(1), Cortes M(2), Schatzman-Bone S(1), Kim AJ(1), Mukhopadhyay B(3), Cinar R(3), Kunos G(3), North TE(4), Goessling W(5).

Author information:

(1)Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

(2)Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. 

(3)Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20982, USA. (4)Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA Harvard Stem Cell Institute, Cambridge, MA 02138, USA. (5)Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Harvard Stem Cell Institute, Cambridge, MA 02138, USA Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Dana-Farber Cancer Institute, Boston, MA 02215, USA Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.