Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein.

Posted on February 17, 2016 by David

“Cannabinoids were shown to induce apoptosis of glioma cells in vitro and tumor regression in vivo…

… we suggest that the increase of proapoptotic Bad activity is an important link between the inhibition of survival pathways and an onset of execution phase of cannabinoid-induced glioma cell death.” http://www.ncbi.nlm.nih.gov/pubmed/15451022

“A glioma is a primary brain tumor that originates from the supportive cells of the brain, called glial cells.” http://neurosurgery.ucla.edu/body.cfm?id=159

“Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death.” http://www.ncbi.nlm.nih.gov/pubmed/15275820

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

Ligands for cannabinoid receptors, promising anticancer agents.

Posted on January 15, 2016 by David

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“Cannabinoid compounds are unique to cannabis and provide some interesting biological properties.

These compounds along with endocannabinoids, a group of neuromodulator compounds in the body especially in brain, express their effects by activation of G-protein-coupled cannabinoid receptors, CB1 and CB2.

There are several physiological properties attributed to the endocannabinoids including pain relief, enhancement of appetite, blood pressure lowering during shock, embryonic development, and blocking of working memory.

On the other hand, activation of endocannabinoid system may be suppresses evolution and progression of several types of cancer.

According to the results of recent studies, CB receptors are over-expressed in cancer cell lines and application of multiple cannabinoid or cannabis-derived compounds reduce tumor size through decrease of cell proliferation or induction of cell cycle arrest and apoptosis along with desirable effect on decrease of tumor-evoked pain.

Therefore, modulation of endocannabinoid system by inhibition of fatty acid amide hydrolase (FAAH), the enzyme, which metabolized endocannabinoids, or application of multiple cannabinoid or cannabis-derived compounds, may be appropriate for the treatment of several cancer subtypes. This review focuses on how cannabinoid affect different types of cancers.”

http://www.ncbi.nlm.nih.gov/pubmed/26764235

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

Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis.

Posted on January 9, 2016 by David

“Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condition, affecting the central nervous system (CNS).

The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mechanisms are not to be underestimated.

The present study was designed to test the effects of intraperitoneal administration of cannabidiol (CBD), the main non-psychotropiccannabinoid of Cannabis sativa (CS), in an experimental model of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of mediators involved in MS-induced apoptosis.

We have demonstrated that, alone, purified CBD possesses an anti-apoptotic power against the neurodegenerative processes underlying MS development. This represents an interesting new profile of CBD that could lead to its introduction in the clinical management of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/26744883

http://www.thctotalhealthcare.com/category/multiple-sclerosis-ms/

Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells.

Posted on December 3, 2015 by David

“The effect of anandamide on human osteoblasts is unclear. This study examined the effect of anandamide on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca2+ levels in MG63 osteosarcoma cells. Anandamide at 50-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that anandamide induced expression of ERK, JNK and p38 MAPK. Anandamide-induced cell death and apoptosis were reversed by SB203580, but not by PD98059 and SP600125, suggesting that anandamide’s action was via p38 MAPK, but not via ERK and JNK. Anandamide at 1-100 microM induced [Ca2+]i increases. Removal of extracellular Ca2+ decreased the anandamide response, indicating that anandamide induced Ca2+ influx and Ca2+ release. Chelation of intracellular Ca2+ with BAPTA reversed anandamide-induced cell death and p38 MAPK phosphorylation. Collectively, in MG63 cells, anandamide induced [Ca2+]i increases which evoked p38 MAPK phosphorylation. This p38 MAPK phosphorylation subsequently activated caspase-3 leading to apoptosis.”

http://www.ncbi.nlm.nih.gov/pubmed/17222495

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

Posted on December 3, 2015 by David

“Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. Osteosarcoma is a bone malignancy that predominantly affects children and adolescents, and exhibits high invasion and metastasis rates.

Although adriamycin (ADM) is an effective benchmark agent for the management of osteosarcoma, it also results in harmful side-effects including toxicity and chemoresistance that substantially affect the quality of life of patients. Therefore, novel therapeutic approaches and drugs must be sought for the treatment of osteosarcoma.

Natural products which have potential antitumor activities have become a focus of attention for study in previous years. Cannabinoids, the active components naturally derived from the marijuana plant Cannabis sativa L., have been reported as potential antitumor drugs based on their ability to limit inflammation, cell proliferation and cell survival.

To date, several cannabinoids have been identified and characterized, including Δ(9)-tetrahydrocannabinol (THC), cannabidiol, cannabinol (CBN) and anandamide, as well as synthetic cannabinoids, including WIN-55,212-2, JWH-133 and (R)-methanandamide.

In the early 1970s, THC and CBN were shown to inhibit tumor growth in Lewis lung carcinoma. Subsequently, cannabinoids were found to induce apoptosis and inhibit the proliferation of various cancer cells, including those of glioma and lymphoma, and prostate, breast, skin and pancreatic cancer…

In conclusion, the present study indicated that cannabinoid WIN-55,212-2 is antiproliferative, antimetastatic and antiangiogenic against MG-63 cells in vitro, and presented evidence that cannabinoid WIN-55,212-2 may result in synergistic antitumor action in combination with ADM against osteosarcoma.

These findings may offer a novel strategy for the treatment of osteosarcoma.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580018/

The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells.

Posted on September 4, 2015 by David

“One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.”

http://www.ncbi.nlm.nih.gov/pubmed/16616335

“Marijuana has been used in medicine for many centuries, and nowadays there is a renaissance in the study of the therapeutic effects of cannabinoids. One of the most active areas of research in the cannabinoid field is the study of the potential antitumoral application of these drugs. Our results unravel the mechanism of cannabinoid antitumoral action by demonstrating the proapoptotic role of the stress protein p8 via its downstream targets ATF-4, CHOP, and TRB3.

The identification of this pathway may contribute to the design of therapeutic strategies for inhibiting tumor growth. In particular, our findings can help to improve the efficiency and selectivity of potential antitumoral therapies with cannabinoids.

Our results also support that cannabinoid treatment does not activate this pathway in nontransformed cells, in line with the belief that cannabinoid proapoptotic action is selective for tumor versus nontumor cells, and that cannabinoids act in a synergic fashion with ER stress inducers as well as with other antitumoral agents.

The identification of the p8-regulated pathway described here may contribute to the design of therapeutic strategies for inhibiting tumor growth. In particular, our findings can help to improve the efficiency and selectivity of a potential cannabinoid-based antitumoral therapy.”

http://www.sciencedirect.com/science/article/pii/S1535610806000857

On the effects of CP 55-940 and other cannabinoid receptor agonists in C6 and U373 cell lines.

Posted on August 10, 2015 by David

“Cannabinoid receptor (CBs) agonists affect the growth of tumor cells via activation of deadly cascades. The spectrum of action of these agents and the precise role of the endocannabinoid system (ECS) on oncogenic processes remain elusive.

Herein we compared the effects of synthetic (CP 55-940 and WIN 55,212-2) and endogenous (anandamide or AEA) CBs agonists (10-20 μM) on morphological changes, cell viability, and induction of apoptosis in primary astrocytes and in two glioblastoma cell lines (C6 and U373 cells) in order to characterize their possible differential actions on brain tumor cells.

None of the CBs agonist tested induced changes in cell viability or morphology in primary astrocytes.

In contrast, CP 55-940 significantly decreased cell viability in C6 and U373 cells at 5 days of treatment, whereas AEA and WIN 55,212-2 moderately decreased cell viability in both cell lines. Treatment of U373 and C6 for 3 and 5 days with AEA or WIN 55,212-2 produced discrete morphological changes in cell bodies, whereas the exposure to CP 55-940 induced soma degradation. CP 55-940 also induced apoptosis in both C6 and U373 cell lines.

Our results support a more effective action of CP 55-940 to produce cell death of both cell lines through apoptotic mechanisms. Comparative aspects between cannabinoids with different profiles are necessary for the design of potential treatments against glial tumors.”

http://www.ncbi.nlm.nih.gov/pubmed/26255146

The role of the peripheral cannabinoid system in the pathogenesis of detrusor overactivity evoked by increased intravesical osmolarity in rats.

Posted on August 6, 2015 by David

“The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO)…

These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction.”

http://www.ncbi.nlm.nih.gov/pubmed/26243021

Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor

Posted on July 13, 2015 by David

“We have previously shown that AEA exerts growth-suppressing effects on cholangiocarcinoma by inducing apoptosis.

At the time, we assumed that AEA was acting via a receptor-independent mechanism.

However, given the recent discovery and characterization of GPR55 as a novel AEA receptor, our data need to be reassessed to determine if GPR55 activation can decrease cholangiocarcinoma cell proliferation.

Thus, our aims are to determine if these AEA-mediated effects on cholangiocarcinoma cell growth can be attributed to the activation of GPR55.

This data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma.

In conclusion, we have clearly demonstrated a role for GPR55 in the antiproliferative effects of AEA in vivo andin vitro…

Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies that target GPR55 may prove beneficial for the treatment of this devastating disease.

Consistent with our observation that AEA has antiproliferative and pro-apoptotic properties, cannabinoids of various origins (endogenous, plant-derived or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126905/

The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration.

Posted on July 13, 2015 by David

“Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma.

The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers.

We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells.

Both cholangiocarcinoma cell lines and surgical specimens from cholangiocarcinoma patients expressed cannabinoid receptors.

THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis.

THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells.

Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.” http://www.ncbi.nlm.nih.gov/pubmed/19916793

“Cholangiocarcinoma is an epithelial cell malignancy arising from varying locations within the biliary tree showing markers of cholangiocyte differentiation. The most contemporary classification based on anatomical location includes intrahepatic, perihilar, and distal cholangiocarcinoma… Understanding of cholangiocarcinoma biology, the oncogenic landscape of this disease, and its complex interaction with the tumour microenvironment could lead to optimum therapies with improvement in patient survival… Hopefully, personalised or precision medicine is in the near future for the treatment of cholangiocarcinoma” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069226/

“Cholangiocarcinomas (bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic, perihilar and extrahepatic bile ducts.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731530/

“Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy after hepatocellular cancer. CC accounts for approximately 10%-25% of all hepatobiliary malignancies. CC is a rare malignancy in Western countries, but more common in Asia. There are several established risk factors for CC, including parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established potential risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125451/

“Cholangiocarcinoma is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long-term inflammation, injury, and reparative biliary epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof-printing workers.” http://www.ncbi.nlm.nih.gov/pubmed/24895231

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