A Review of the Therapeutic Antitumor Potential of Cannabinoids.

:Image result for J Altern Complement Med.

“The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment.

RESULTS:

Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of “cannabinoid sensitizers.” Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness.

CONCLUSIONS:

A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with standard anticancer strategies. With such knowledge, cannabinoids could become a therapy of choice in contemporary oncology.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabinoids as Modulators of Cell Death: Clinical Applications and Future Directions.

 Image result for Rev Physiol Biochem Pharmacol.

“Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic cannabinoids mimic the effects of endocannabinoids.

In recent years, a growing interest has been dedicated to the study of cannabinoids properties for their analgesic, antioxidant, anti-inflammatory and neuroprotective effects. In addition to these well-recognized effects, various studies suggest that cannabinoids may affect cell survival, cell proliferation or cell death. These observations indicate that cannabinoids may play an important role in the regulation of cellular homeostasis and, thus, may contribute to tissue remodelling and cancer treatment.

For a long time, the study of cannabinoid receptor signalling has been focused on the classical adenylyl cyclase/cyclic AMP/protein kinase A (PKA) pathway. However, this pathway does not totally explain the wide array of biological responses to cannabinoids. In addition, the diversity of receptors and signalling pathways that endocannabinoids modulate offers an interesting opportunity for the development of specific molecules to disturb selectively the endogenous system.

Moreover, emerging evidences suggest that cannabinoids ability to limit cell proliferation and to induce tumour-selective cell death may offer a novel strategy in cancer treatment.

This review describes the main properties of cannabinoids in cell death and attempts to clarify the different pathways triggered by these compounds that may help to understand the complexity of respective molecular mechanisms and explore the potential clinical benefit of cannabinoids use in cancer therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/28425013

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis.

“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis.

CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

For multifactorial chronic diseases, such as fibrosis, the conventional pharmacological approach based on the “one-disease/one-target/one-drug” paradigm limits therapeutic efficacy and could be improved by simultaneously hitting multiple therapeutic targets.

One such target is the endocannabinoid/cannabinoid-1 receptor (endocannabinoid/CB1R) system.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases .

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979564/

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects.

Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

Regarding the pharmacodynamics of the hybrid CB1R/iNOS inhibitor, two important principles have emerged from efforts to develop effective antifibrotic therapies. First, antifibrotic treatment strategies could aim to control the primary disease, to inhibit fibrogenic gene expression and signaling, to promote molecular mechanisms involved in fibrosis regression, or a combination of these. Second, with multiple molecular mechanisms and signaling pathways involved in fibrosis, targeting more than one could increase antifibrotic efficacy, and the hybrid CB1R/iNOS inhibitor embodies optimal characteristics on both accounts.

As to the first principle, both the endocannabinoid/CB1R system and iNOS are ideal targets, as they are known to be involved directly in the fibrotic process and also in the conditions predisposing to liver fibrosis, as detailed in the Introduction. An emerging major predisposing factor to liver fibrosis is nonalcoholic fatty liver disease, and CB1R blockade has proven effective in mitigating obesity-related hepatic steatosis in both rodent models and humans. The other two major predisposing factors, alcoholic fatty liver disease and viral hepatitis, also involve increased CB1R activity. Hepatic CB1R expression is induced either by chronic ethanol intake or the hepatitis C virus, and CB1R blockade mitigates alcohol-induced steatosis and inhibits hepatitis C virus production.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases.

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

http://insight.jci.org/articles/view/87336

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.

“The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC).

Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive.

CONCLUSIONS:

Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.”

http://www.ncbi.nlm.nih.gov/pubmed/27196571

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

[Cannabinoid WIN55, 212-2 inhibits proliferation, invasion and migration of human SMMC-7721 hepatocellular carcinoma cells].

“Objective To investigate the effects of WIN55, 212-2 (WIN) on the proliferation, invasion and migration of SMMC-7721 hepatocellular carcinoma cells and its underlying mechanisms. Methods SMMC-7721 cells were treated with (0, 1, 5, 10, 20) μmol/L WIN, and cell viability was determined by CCK-8 assay. The morphological changes of the cells were observed under a fluorescence microscope with Hoechst33258 staining. Cell apoptosis was measured by flow cytometry combined with annexin V-FITC/PI staining. The expression levels of apoptosis-related proteins P53, P21, Bcl-2 and Bax, and the phosphorylated AKT (p-AKT) and phosphorylated extracellular signal-regulated kinase (p-ERK) were analyzed by Western blotting. Transwell(TM) invasion assay was used to detect cell invasion ability. Would healing assay was performed to test cell migration ability. The expression level of matrix metalloproteinase 14 (MMP-14) was evaluated by Western blotting. Results WIN inhibited the proliferation of SMMC-7721 cells and induced cell apoptosis in a dose-dependent manner. After treatment with WIN, the cell nucleus concentrated and broken, indicating obvious cell apoptosis. Western blotting exhibited an up-regulation in the protein expression of P53, P21 and Bax. And the anti-apoptotic protein Bcl-2 was repressed. The expression levels of AKT, p-AKT and p-ERK were down-regulated, whereas the expression of total ERK was not obviously changed. Compared with control group, there was a significant inhibition of cell invasion and migration abilities when SMMC-7721 cells were treated with WIN. The expression level of MMP-14 decreased as well. Conclusion WIN can inhibit the proliferation of SMMC-7721 cells and induce cell apoptosis. The mechanism is associated with the activation of P53 and the inhibition of AKT, p-AKT and p-ERK. WIN can inhibit the invasion and migration of SMMC-7721 cells through down-regulating the protein expression of MMP-14.”

http://www.ncbi.nlm.nih.gov/pubmed/27126940

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells.

“HBV represents the most common chronic viral infection and major cause of hepatocellular carcinoma (HCC), although its exact role in liver tumorigenesis is unclear. Massive storage of the small (SHBs), middle (MHBs) and large surface (LHBs) HBV envelope proteins leads to cell stress and sustained inflammatory responses. Cannabinoid (CB) system is involved in the pathogenesis of liver diseases, stimulating acute and chronic inflammation, liver damage and fibrogenesis; it triggers endoplasmic reticulum (ER) stress response. The aim of our work was to investigate the activation of ER stress pathway after ectopic HBV envelope proteins expression, in liver cancer cells, and the role exerted by CB receptors. PCR, immunofluorescence and western blotting showed that exogenous LHBs and MHBs induce a clear ER stress response in Huh-7 cells expressing CB1 receptor. Up-regulation of the chaperone BiP/GRP78 (Binding Immunoglobulin Protein/Glucose-Regulated Protein 78) and of the transcription factor CHOP/GADD153 (C/EBP Homologous Protein/Growth Arrest and DNA Damage inducible gene 153), phosphorylation of PERK (PKR-like ER Kinase) and eIF2α (Eukaryotic Initiation Factor 2α) and splicing of XBP1 (X-box binding protein 1) was observed. CB1-/- HepG2 cells did not show any ER stress activation. Inhibition of CB1 receptor counteracted BiP expression in transfected Huh-7 and in HBV+ PLC/PRF/5 cells; whereas no effect was observed in HBV- HLF cells. These results suggest that HBV envelope proteins are able to induce the ER stress pathway. CB1 expression is directly correlated with ER stress function. Further investigations are needed to clarify the involvement of cannabinoid in HCC progression after HBV infection.”

http://www.ncbi.nlm.nih.gov/pubmed/26967385

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

Image result for Eur J Pharmacol.

“Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis.

Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies.

Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects.

The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer.

Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address.”

http://www.ncbi.nlm.nih.gov/pubmed/26852955

http://www.thctotalhealthcare.com/category/cancer/

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous