Category Archives: Gliomas

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

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“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/

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

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“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/

The G1359A-CNR1 gene polymorphism is associated to glioma in Spanish patients.

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“The cannabinoid receptor gene 1 (CNR1) encodes the human cannabinoid receptor CB1.

This receptor has a widespread distribution in the central nervous system (CNS), the main ligands being anandamide, 2-araquidonoil glycerol and marijuana constituents.

There is evidence to suggest an anti-neoplastic effect of these ligands in glial tissues mediated through stimulation of the receptor.

Our results suggest that allele G of the CNR1 gene could be associated with a lower susceptibility to glioma.”

http://www.ncbi.nlm.nih.gov/pubmed/21156413

“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

“Cannabinoids, the active components of Cannabis sativa…”  http://www.ncbi.nlm.nih.gov/pubmed/17952650

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

Ligands for cannabinoid receptors, promising anticancer agents.

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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/

Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells.

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“Cannabinoids possess a number of characteristics that make them putative anticancer drugs, and their value as such is currently being explored in a number of clinical studies.

To further understand the roles that cannabinoids may have, we performed gene expression profiling in glioma cell lines cultured with cannabidiol (CBD) and/or Δ9-tetrahydrocannabinol (THC), and pursued targets identified by this screening.

Results showed that a large number of genes belonging to the heat shock protein (HSP) super-family were up-regulated following treatment, specifically with CBD. Increases were observed both at the gene and protein levels and arose as a consequence of increased generation of ROS by CBD, and correlated with an increase in a number of HSP client proteins. Furthermore, increases impeded the cytotoxic effect of CBD; an effect that was improved by co-culture with pharmacalogical inhibitors of HSPs. Similarly, culturing glioma cells with CBD and HSP inhibitors increased radiosensitivity when compared to CBD-alone.

Taken together, these data indicate that the cytotoxic effects of CBD can be diminished by HSPs that indirectly rise as a result of CBD use, and that the inclusion of HSP inhibitors in CBD treatment regimens can enhance the overall effect.”

http://www.ncbi.nlm.nih.gov/pubmed/26504004

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

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“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 use of cannabinoids as anticancer agents.

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“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer.

Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death.

In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration.

The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.

In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989

“… cannabinoids have been shown to alleviate nausea and vomit induced by chemotherapy and several cannabinoid-based medicines [Marinol (THC) and Cesamet (nabilone, a synthetic analogue of THC)] are approved for this purpose. Cannabinoids also inhibit pain, and Sativex (a standardized cannabis extract) has been approved in Canada for the treatment of cancer-associated pain. Other potential palliative effects of cannabinoids in oncology include appetite stimulation and attenuation of wasting. In addition to these palliative actions of cannabinoids in cancer patients, THC and other cannabinoids exhibit antitumour effects in animal models of cancer… a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer… In conclusion there exist solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical studies aimed at testing them as single agents or in combinational therapies are urgently needed.” http://www.sciencedirect.com/science/article/pii/S0278584615001190

Marijuana kills brain cancer, new study confirms

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“The active molecules in cannabis kill brain cancer — another study has revealed.”

“Scientists using an extract of whole-plant marijuana rich in pot’s main psychoactive ingredient THC as well as cannabidiol (CBD) showed “dramatic reductions in tumor volumes” of a type of brain cancer.”  http://blog.sfgate.com/smellthetruth/2014/11/18/marijuana-kills-brain-cancer-new-study-confirms/

“Marijuana kills brain cancer, new study confirms. The active molecules in cannabis kill brain cancer — another study has revealed.” http://blog.seattlepi.com/marijuana/2014/11/18/marijuana-kills-brain-cancer-new-study-confirms/#13130101=0

“Marijuana Kills Brain Cancer Cells. Researchers have found that the THC in marijuana causes brain cancer cells to die in both mice and humans.”  http://www.nbcphiladelphia.com/news/health/Marijuana_Kills_Brain_Cancer_Cells_All__National_.html

“Marijuana Kills Brain Cancer, New Study Confirms” http://cancerguide.byethost8.com/marijuana-kills-brain-cancer-new-study-confirms-sfgate-blog/

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

Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients’ cells.

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“Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas…

These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.

CB1 is implicated in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in several physio-pathological conditions. We shed light on previously unrecognized molecular mechanism of CB1-mediated modulation of human glioma progression and provide the first and original demonstration of CB1-STAT3 axis as a new target and predictor biomarkers of the benefit from specific therapies.

Indeed CB1 antagonism capable of tumoral cell division’ control while making the glioma immunovisible and engaging the immune system to fight it may represent a hopeful alternative to other established chemotherapeutics.

Because different aspects of glioma biology have been separately targeted with very limited success, we speculate that CB1 inhibitors which enclose in the same molecule cytotoxic potential and high activity to boost competent immune surveillance mechanisms, at a degree that seems to be correlated to the levels of CB1 immunoreactivity, might have profound implications for exploring new therapeutic anti-glioma actions.”

http://www.ncbi.nlm.nih.gov/pubmed/26008966

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

Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.

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Figure 2

“Glioblastoma (GBM) is the most common form of primary adult brain tumors…

It is, therefore, essential to discover master regulators that control GBM invasiveness and target them therapeutically.

We demonstrate here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of GBM cell lines and primary GBM cells.

Furthermore, we show that a non-toxic compound, cannabidiol, significantly down-regulates Id-1 gene expression and associated glioma cell invasiveness…

Our results suggest that Id-1 regulates multiple tumor-promoting pathways in GBM, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of GBM patients.

We previously showed a strong correlation between Id-1 expression and the invasive and metastatic behavior of breast cancer cells.”

“Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells… CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells…  Moreover, reducing Id-1 expression with cannabinoids could also provide a therapeutic strategy for the treatment of additional aggressive cancers because Id-1 expression was found to be up-regulated during the progression of almost all types…”  http://mct.aacrjournals.org/content/6/11/2921.long

“In this report, we show that Id-1 is a key regulator of brain tumor cell invasiveness and neurosphere growth, and that Id-1 expression is specifically up-regulated in tissues from patients with high-grade gliomas. Importantly, we demonstrate that targeting Id-1 expression using either genetic approaches or the non-toxic cannabinoid, cannabidiol (CBD), leads to a significant reduction in the invasion of both GBM cell lines and patient-derived primary GBM cultures. CBD also significantly inhibits GBM dispersal ex vivo, and reduces tumor growth and Id-1 expression in vivo.

Consistent with the breast cancer study, we found that the non-psychoactive cannabinoid CBD significantly down-regulated Id-1 expression in serum-derived and primary GBM cells. As expected, we observed robust inhibition of glioma cell invasiveness.

In conclusion, our results establish Id-1 as a key regulator of both invasion and stemness in GBM cells and demonstrate that the non-toxic cannabinoid compound CBD down-regulates Id-1 expression and tumor aggressiveness in culture and in vivo.

The data also shed light on some of the key pathways that control GBM cell dispersal and progression. A greater understanding of these pathways may lead to more effective therapies for cancer patients including the additional refinement of cannabinoid analogs targeting Id-1.

We expect our efforts to ultimately translate to the development of future clinical trials with nontoxic compounds that target the expression of Id-1, a master regulator of GBM aggressiveness.

With its lack of systemic toxicity and psychoactivity, CBD is an ideal candidate agent in this regard and may prove useful in combination with front-line agents for the treatment of patients with aggressive and high-grade GBM tumors.”  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594064/

“McAllister Lab… Cannabidiol inhibits tumor (glioblastoma) progression in mouse models of brain cancer. Mice bearing human brain tumors derived from glioblastoma were treated with the naturally occurring cannabinoid, cannabidiol (CBD).”  http://www.cpmcri-currents.org/our-people/discovery-investigators/mcallister-lab

“New Study Finds Cannabis Compound Could Have Even Greater Reach in Inhibiting Aggressive Cancer than Previously Thought. Researchers at California Pacific Medical Center Research Institute (CPMCRI, a Sutter Health affiliate) have found that a compound in cannabis previously shown to decrease metastatic breast cancer now shows promise in stopping aggressive brain cancer as well. The findings are particularly important given the safety of the cannabis compound and the fact that patients with advanced brain cancer have few options for treatment.”  http://www.cpmc.org/about/press/news2012/cannabis-brain.html

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

Glioblastoma progression in mouse models of brain cancer, after treatment with CBD