INSIGHT ON THE IMPACT OF ENDOCANNABINOID SYSTEM IN CANCER: A REVIEW.

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“In the last decades, the endocannabinoid system has attracted a great interest in medicine and cancer disease is probably one of its most promising therapeutic areas.

On the one hand, endocannabinoid system expression has been found altered in numerous types of tumours compared to healthy tissue, and this aberrant expression has been related to cancer prognosis and disease outcome, suggesting a role of this system in tumour growth and progression that depends on cancer type.

On the other hand, it has been reported that cannabinoids exert an anticancer activity by inhibiting the proliferation, migration and/or invasion of cancer cells; and also tumour angiogenesis.

The endocannabinoid system may be considered as a new therapeutic target, although further studies to fully establish the effect of cannabinoids on tumour progression remain necessary.”

https://www.ncbi.nlm.nih.gov/pubmed/29663308

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Cannabis and Anti-Cancer Drugs: Societal Usage and Expected Pharmacological Interactions – A Review.

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“Cannabis is a plant that has been used for centuries to relieve a wide range of symptoms. Since the 1960s, interest in medical research into this plant has grown steadily. Already very popular for recreational use, a growing number of consumers not accustomed to using cannabis for psychoactive purposes, have begun to use it as an alternative or complement to mainstream pharmaceutical medicines. The principal unsubstantiated or “social” uses of cannabis are based mainly on data that is at best controversial, but usually not scientifically proven. The aim of this review is to identify the scientific basis and reasons that lead patients with cancer to consume cannabis, and also to identify whether there is a risk of interaction between cannabis and anti-cancer medicines through drug transporters (P-glycoprotein and other ABC-superfamily members) Cytochromes P450 (3A, 1A, 2B, 2C 2D families…) and glucuronyl-transferases.”

https://www.ncbi.nlm.nih.gov/pubmed/29660159

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12373

“Cannabinoids as Anticancer Drugs.”  https://www.ncbi.nlm.nih.gov/pubmed/28826542

“Targeting the endocannabinoid system as a potential anticancer approach.”  https://www.ncbi.nlm.nih.gov/pubmed/29390896

“Anticancer mechanisms of cannabinoids”   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/

http://www.thctotalhealthcare.com/tag/anticancer/

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The use of cannabis in supportive care and treatment of brain tumor

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“Anticancer Effects of Cannabinoids may be able to Prolong Life.

Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC.

Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive.

Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.

THC, a partial CB1, CB2 agonist, has the stigma of psychotropic effects that are mediated by CB1 stimulation. However, CB1 stimulation is necessary for improving mood and appetite and many other effects. At present, it is hard to imagine a better approach than adjusting THC doses individually to balance wanted versus unwanted effects. Generally, higher doses are needed to achieve analgesic and antiemetic effects. Even much higher, supraphysiologic oral doses would be needed to combat tumors.

Combinations were synergistic under many circumstances such as in pain and antitumor studies. Cannabinoids differ in their antitumor activities and probably in their mechanisms and targets, which is a rationale for combinations. However, for many pharmacological effects (except against tumors) roughly 10-times higher daily doses are needed for CBD compared to THC.

In summary, the endocannabinoid system is likely playing a crucial role in palliative care. The future will show whether an optimized treatment strategy with cannabinoids can also prolong life of brain tumor patients by their virtue to combat cancer cells.”

https://academic.oup.com/nop/article/4/3/151/2918616

“Cannabinoid Drug Prolongs the Life of Brain Tumor Patients in Phase II Trials”  https://labiotech.eu/gw-pharmaceuticals-brain-tumor/

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The current state and future perspectives of cannabinoids in cancer biology.

Cancer Medicine

“To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. In this review, we present an actual state of knowledge regarding molecular mechanisms of cannabinoids’ anticancer action, but we discuss also aspects that are still not fully understood such as the role of the endocannabinoid system in a carcinogenesis, the impact of cannabinoids on the immune system in the context of cancer development, or the cases of a stimulation of cancer cells’ proliferation by cannabinoids. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents.”

https://www.ncbi.nlm.nih.gov/pubmed/29473338

http://onlinelibrary.wiley.com/doi/10.1002/cam4.1312/abstract

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CBD Enhances the Anticancer Effects of THC

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“Δ9-Tetrahydrocannabinol (Δ9-THC) and other cannabinoids can act as direct anticancer agents in multiple types of cancer in culture and in vivo.
Cannabidiol Enhances the Inhibitory Effects of  Δ9-Tetrahydrocannabinol on Human GlioblastomaCell Proliferation and Survival.
Δ9-THC and Cannabidiol Inhibit the Growth of Multiple Glioblastoma Cell Lines.
Cannabidiol Enhances the Inhibitory Effects of Δ9-THC on Glioblastoma Cell Growth.
Combination treatments with cannabinoids may improve overall efficacy”

“Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival”   http://mct.aacrjournals.org/content/9/1/180.full

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Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.

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“Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells.

Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells.

Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death.

Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance.

Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD.

Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD.

The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/24309936

“The non-psychoactive plant cannabinoid, cannabidiol (CBD), alone has strong anti-inflammatory and immunosuppressive effects in diverse animal models of disease such as diabetes, cancer, rheumatoid arthritis and multiple sclerosis. In addition, CBD has been reported to have anxiolytic, antiemetic and antipsychotic effects. Moreover, CBD has been shown to possess antitumor activity in human breast carcinoma and to effectively reduce primary tumor mass, as well as size and number of lung metastasis in preclinical animal models of breast cancer.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877544/

“In summary, in this study we have identified VDAC1 as a new molecular target for CBD. Our study suggests that CBD-induced cell death may occur through the inhibition of VDAC1 conductance and that this interaction may be responsible for the anticancer and immunosuppressive properties of CBD.”

https://www.nature.com/articles/cddis2013471

“Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-CancerTherapeutics.” https://www.ncbi.nlm.nih.gov/pubmed/28824871

“Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target.”  https://www.ncbi.nlm.nih.gov/pubmed/25448878

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Cannabidiol Induces Cytotoxicity and Cell Death via Apoptotic Pathway in Cancer Cell Lines

“In view of obtaining potential anticancer compounds, we studied the inhibitory activity and the cytotoxic effects of a candidate compound in cancer cells. The cytotoxic effects of cannabidiol (CBD) in vitro were evaluated in NIH3T3 fibroblasts, B16 melanoma cells, A549 lung cancer cells, MDA-MB-231 breast cancer cells, Lenca kidney cells and SNU-C4 colon cancer cells.
The inhibitory activity of CBD was increased in all cancer cells and showed especially strong increment in breast cancer cells. The cytotoxicity of CBD increased in a dose- and time-dependent manner with growth inhibition in all cancer cell lines.
Therefore these results suggest that CBD has a possibility of anticancer agents and anticancer effects against cancer cells by modulation of apoptotic pathway in the range of 5-80 μM concentration.”
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Targeting the endocannabinoid system as a potential anticancer approach.

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“The endocannabinoid system is currently under intense investigation due to the therapeutic potential of cannabinoid-based drugs as treatment options for a broad variety of diseases including cancer.

Besides the canonical endocannabinoid system that includes the cannabinoid receptors CB1 and CB2 and the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, recent investigations suggest that other fatty acid derivatives, receptors, enzymes, and lipid transporters likewise orchestrate this system as components of the endocannabinoid system when defined as an extended signaling network.

As such, fatty acids acting at cannabinoid receptors (e.g. 2-arachidonoyl glyceryl ether [noladin ether], N-arachidonoyldopamine) as well as endocannabinoid-like substances that do not elicit cannabinoid receptor activation (e.g. N-palmitoylethanolamine, N-oleoylethanolamine) have raised interest as anticancerogenic substances.

Furthermore, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid binding protein family, additional cannabinoid-activated G protein-coupled receptors, members of the transient receptor potential family as well as peroxisome proliferator-activated receptors have been considered as targets of antitumoral cannabinoid activity. Therefore, this review focused on the antitumorigenic effects induced upon modulation of this extended endocannabinoid network.” https://www.ncbi.nlm.nih.gov/pubmed/29390896  http://www.tandfonline.com/doi/abs/10.1080/03602532.2018.1428344?journalCode=idmr20

“Anticancer mechanisms of cannabinoids”   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/
“Cannabinoids as Anticancer Drugs.”
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The Synthetic Cannabinoid WIN 55,212-2 Elicits Death in Human Cancer Cell Lines.

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“Studies have revealed that cancer might be treated with cannabinoids since they can influence cancer cell survival. These findings suggest an alternative treatment option to chemo- and radiotherapy, that are associated with numerous adverse side-effects for the patients.

MATERIALS AND METHODS:

Viability staining was conducted on lung cancer, testicular cancer and neuroblastoma cells treated with different concentrations of the synthetic cannabinoid WIN 55,212-2 and the percentage of dead cells was compared. Activity of apoptosis-related enzymes was investigated by the presence of DNA ladder in gel electrophoresis.

RESULTS:

Treatment with different WIN 55,212-2 concentrations led to a significant dose-dependent reduction of cell viability. A DNA ladder was observed after WIN 55,212-2 treatment of testicular cancer and lung cancer cells.

CONCLUSION:

The application of WIN 55,212-2 was found to trigger cell death in the investigated cell lines. The decline in lung cancer and testicular cancer cell viability seems to have been caused by apoptosis. These findings may contribute to development of alternative cancer therapy strategies.”

https://www.ncbi.nlm.nih.gov/pubmed/29061818

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Cannabinoids as Anticancer Drugs.

Advances in Pharmacology

“The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.sciencedirect.com/science/article/pii/S105435891730039X?via%3Dihub

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