Category Archives: Gliomas

Cannabidiol Affects Extracellular Vesicle Release, miR21 and miR126, and Reduces Prohibitin Protein in Glioblastoma Multiforme Cells.

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 Translational Oncology“Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumor in adults, with poor prognosis. Extracellular vesicles (EVs) are key-mediators for cellular communication through transfer of proteins and genetic material. Cancers, such as GBM, use EV release for drug-efflux, pro-oncogenic signaling, invasion and immunosuppression; thus the modulation of EV release and cargo is of considerable clinical relevance. As EV-inhibitors have been shown to increase sensitivity of cancer cells to chemotherapy, and we recently showed that cannabidiol (CBD) is such an EV-modulator, we investigated whether CBD affects EV profile in GBM cells in the presence and absence of temozolomide (TMZ). Compared to controls, CBD-treated cells released EVs containing lower levels of pro-oncogenic miR21 and increased levels of anti-oncogenic miR126; these effects were greater than with TMZ alone. In addition, prohibitin (PHB), a multifunctional protein with mitochondrial protective properties and chemoresistant functions, was reduced in GBM cells following 1 h CBD treatment. This data suggests that CBD may, via modulation of EVs and PHB, act as an adjunct to enhance treatment efficacy in GBM, supporting evidence for efficacy of cannabinoids in GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/30597288

“Cannabidiol (CBD) is a phytocannabinoid derived from Cannabis sativa and known for its anti-neoplastic and chemo-preventive activities. Known anti-cancerous effects of cannabinoids include inhibition of tumor proliferation, angiogenesis and induction of tumor cell death, while in GBM, additional effects on inhibition of invasiveness and stem-cell like properties have been observed. CBD has also been shown to selectively inhibit GBM proliferation and to induce death of cultured human GBM cells, as well as being effective against other cancers.  We have recently shown that CBD is a novel modulator of EV release in several cancer cell lines and we and other groups have shown that EV-modulators, including CBD, can significantly increase sensitivity of various cancer cells to chemotherapy. This supports emerging evidence that CBD has anti-cancer effects and indicates that CBD can be used to lower anti-chemotherapeutic responses to TMZ as well as modifying EV cargo to an anti-oncogenic signature in GBM.”

https://www.sciencedirect.com/science/article/pii/S1936523318305990?via%3Dihub

Lipid nanocapsules decorated and loaded with cannabidiol as targeted prolonged release carriers for glioma therapy: in vitro screening of critical parameters.

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 European Journal of Pharmaceutics and Biopharmaceutics“The therapeutic potential of cannabinoids has been truly constrained heretofore due to their strong psychoactive effects and their high lipophilicity. In this context, precisely due to the lack of psychoactive properties, cannabidiol (CBD), the second major component of Cannabis sativa, arises as the phytocannabinoid with the most auspicious therapeutic potential.

Hence, the incorporation of CBD in lipid nanocapsules (LNCs) will contribute to overcome the dosing problems associated with cannabinoids.

Herein, we have prepared LNCs decorated and loaded with CBD for glioma therapy and screened in vitro their critical parameters. On the one hand, we have encapsulated CBD into the oily core of LNCs to test their in vitro efficacy as extended-release carriers against the human glioblastoma cell line U373MG. The in vitro antitumor effect was highly dependent on the size of LNCs due to its pivotal role in the extent of CBD release.

Effectively, a comparison between two differently-sized LNCs (namely, 20-nm and 50-nm sized carriers) showed that the smaller LNCs reduced by 3.0-fold the IC50 value of their 50-nm sized counterparts. On the other hand, to explore the potential of this phytocannabinoid to target any of the cannabinoid receptors overexpressed in glioma cells, we decorated the LNCs with CBD. This functionalization strategy enhanced the in vitro glioma targeting by 3.4-fold in comparison with their equally-sized undecorated counterparts.

Lastly, the combination of CBD-loading with CBD-functionalization further reduced the IC50 values. Hence, the potential of these two strategies of CBD incorporation into LNCs deserves subsequent in vivo evaluation.”

https://www.ncbi.nlm.nih.gov/pubmed/30472144

https://www.sciencedirect.com/science/article/abs/pii/S0939641118311366?via%3Dihub

Cannabis Therapeutics and the Future of Neurology.

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“Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes.

While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain.

This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE).

Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics.

The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30405366

https://www.frontiersin.org/articles/10.3389/fnint.2018.00051/full

Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol.

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“Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet.

The aim of this study was to assess the effects of pharmaceutical-grade synthetic cannabidiol on a range of cancer patients.

RESULTS:

Clinical responses were seen in 92% of the 119 cases with solid tumours including a reduction in circulating tumour cells in many cases and in other cases, a reduction in tumour size, as shown by repeat scans. No side-effects of any kind were observed when using pharmaceutical grade synthetic cannabidiol.

CONCLUSION:

Pharmaceutical-grade synthetic cannabidiol is a candidate for treating breast cancer and glioma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30275207

http://ar.iiarjournals.org/content/38/10/5831

Targeting Glioma Initiating Cells With A Combined Therapy Of Cannabinoids And Temozolomide.

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Biochemical Pharmacology

“Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease.

Previous observations by our group and others have shown that Δ9-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas.

We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts.

In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs.

Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts.

Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations – and specifically those containing a higher proportion of CBD – may be therapeutically explored to target the population of GICs in GBM.”

 https://www.ncbi.nlm.nih.gov/pubmed/30195736
https://www.sciencedirect.com/science/article/abs/pii/S0006295218303897

Optimization Of A Preclinical Therapy Of Cannabinoids In Combination With Temozolomide Against Glioma.

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 Biochemical Pharmacology “Glioblastoma multiforme (GBM) is the most frequent and aggressive form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease.

Δ9-Tetrahydrocannabinol (THC, the major active ingredient of marijuana), and other cannabinoids have been shown to exert antitumoral actions in animal models of cancer, including glioma. The mechanism of these anticancer actions relies, at least in part, on the ability of these compounds to stimulate autophagy-mediated apoptosis in tumor cells.

Previous observations from our group demonstrated that local administration of THC (or of THC + CBD at a 1:1 ratio, a mixture that resembles the composition of the cannabinoid-based medicine Sativex®) in combination with Temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts.

With the aim of optimizing the possible clinical utilization of cannabinoids in anti-GBM therapies, in this work we explored the anticancer efficacy of the systemic administration of cannabinoids in combination with TMZ in preclinical models of glioma.

Our results show that oral administration of THC+CBD (Sativex-like extracts) in combination with TMZ produces a strong antitumoral effect in both subcutaneous and intracranial glioma cell-derived tumor xenografts. In contrast, combined administration of Sativex-like and BCNU (another alkylating agent used for the treatment of GBM which share structural similarities with the TMZ) did not show a stronger effect than individual treatments.

Altogether, our findings support the notion that the combined administration of TMZ and oral cannabinoids could be therapeutically exploited for the management of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/30125556

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303496

Current natural therapies in the treatment against glioblastoma.

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Phytotherapy Research banner

“Glioblastoma (GBM) is the most common and aggressive brain tumor, which causes the highest number of deaths worldwide. It is a highly vascularized tumor, infiltrative, and its tumorigenic capacity is exacerbated. All these hallmarks are therapeutic targets in GBM treatment, including surgical removal followed by radiotherapy and chemotherapy.

Current therapies have not been sufficient for the effective patient’s management, so the classic therapies have had to expand and incorporate new alternative treatments, including natural compounds.

This review summarizes natural products and their physiological effects in in vitro and in vivo models of GBM, specifically by modulating signaling pathways involved in angiogenesis, cell migration/invasion, cell viability, apoptosis, and chemoresistance. The most important aspects of natural products and their derivatives were described in relation to its antitumoral effects.

As a final result, it can be obtained that within the compounds with more evidence that supports or suggests its clinical use are the cannabinoids, terpenes, and curcumin, because many have been shown to have a significant effect in decreasing the progress of GBM through known mechanisms, such as chemo-sensitization or decrease migration and cell invasion.

Natural compounds emerge as promising therapies to attack the progress of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/30109743
https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6170

Anti-tumoural actions of cannabinoids.

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“The endocannabinoid system has emerged as a considerable target for the treatment of diverse diseases.

In addition to the well-established palliative effects of cannabinoids in cancer therapy, phytocannabinoids, synthetic cannabinoid compounds as well as inhibitors of endocannabinoid degradation have attracted attention as possible systemic anticancer drugs.

As a matter of fact, accumulating data from preclinical studies suggest cannabinoids elicit effects on different levels of cancer progression, comprising inhibition of proliferation, neovascularisation, invasion and chemoresistance, induction of apoptosis and autophagy as well as enhancement of tumour immune surveillance.

Although the clinical use of cannabinoid receptor ligands is limited by their psychoactivity, nonpsychoactive compounds, such as cannabidiol, have gained attention due to preclinically established anticancer properties and a favourable risk-to-benefit profile.

Thus, cannabinoids may complement the currently used collection of chemotherapeutics, as a broadly diversified option for cancer treatment, while counteracting some of their severe side effects.” https://www.ncbi.nlm.nih.gov/pubmed/30019449

“During the last few decades, a large body of evidence has accumulated to suggest endocannabinoids, phytocannabinoids and synthetic cannabinoids exert an inhibitory effect on cancer growth via blockade of cell proliferation and induction of apoptosis. Some studies support the hypothesis that cannabinoids may enhance immune responses against the progressive growth and spread of tumours.”  https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14426#bph14426-fig-0001
“Previous research has shown that cannabinoids can help lessen side effects of anti-cancer therapies. Now a new British Journal of Pharmacology review has examined their potential for the direct treatment of cancer. Studies have shown that cannabinoids may stop cancer cells from dividing and invading normal tissue, and they may block the blood supply to tumors. Some studies also indicate that cannabinoids may enhance the body’s immune response against the growth and spread of tumors.” https://www.eurasiareview.com/19072018-cannabinoids-may-have-a-vast-array-of-anti-cancer-effects/
“Cannabinoids may have a vast array of anti-cancer effects” https://www.sciencedaily.com/releases/2018/07/180718082143.htm

“Cannabinoids may have a vast array of anti-cancer effects”  https://www.eurekalert.org/pub_releases/2018-07/w-cmh071718.php

“Marijuana may help fight cancer” https://nypost.com/2018/07/18/marijuana-may-help-fight-cancer/

“Cannabis stops cancer spreading and boosts immune system, say scientists. Studies show cannabinoids can stop cancer cells from dividing and spreading, and blocks blood supply to tumours” https://www.plymouthherald.co.uk/news/health/cannabis-can-cure-cancer-proof-1803485
“Cannabis stops cancer spreading and boosts immune system, say scientists. Cannabis can act as a treatment for cancer and boost the immune system, claims a new study.” https://www.devonlive.com/news/health/cannabis-can-cure-cancer-proof-1803485
“Cannabis stops cancer spreading and boosts immune system, say scientists. Cannabis can act as a treatment for cancer and boost the immune system, claims a new study.” https://www.cornwalllive.com/news/uk-world-news/cannabis-can-cure-cancer-proof-1803485
“Cannabis ‘can act as a treatment for cancer’. Cannabis can enhance the immune system and act as a treatment for cancer, claims a new study. Scientists at Rostock University Medical Centre in Germany claimed the benefits following a review of more than 100 studies.” https://www.thelondoneconomic.com/news/cannabis-can-act-as-a-treatment-for-cancer/19/07/

Cannabinoids as potential new therapy for the treatment of gliomas

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“Gliomas constitute the most frequent and malignant primary brain tumors. Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics, e.g., temozolomide, carmustin or carboplatin) for their treatment are only palliative and survival diagnosis is normally 6-12 months.
The development of new therapeutic strategies for the management of gliomas is therefore essential.
Interestingly, cannabinoids have been shown to exert antiproliferative effects on a wide spectrum of cells in culture.
Of interest, cannabinoids have displayed a great potency in reducing glioma tumor growth either in vitro or in animal experimental models, curbing the growth of xenografts generated by subcutaneous or intratecal injection of glioma cells in immune-deficient mice.
Moreover, cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts.
A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.”

Cannabinoids as a Promising Therapeutic Approach for the Treatment of Glioblastoma Multiforme: A Literature Review

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“Gliobalstoma multiforme (GBM) or grade 4 astrocytoma is the most malignant form of primary brain tumor. Treatment of glioblastoma is difficult despite of surgery, radiotherapy and chemotherapy. Patients with glioblastoma survive for less than 12 months.

Considering to biology function of glioblastoma, researchers have recently offered new therapeutic approaches such as cannabinoid therapy for glioblastoma.

Cannabinoids are active compounds of Cannabis sativa that operate in the body similar to endogenous canabinoids –the endocannabinoids- through cell surface receptors.

It is interesting that cannabinoids could exert a wide spectrum from antiproliferative effects in condition of the cell culture, animal models of glioblastoma and clinical trials.

As a result, Cannabinoids seem to modulate intracellular signaling pathways and the endoplasmic reticulum stress response in glioma cells.

Those play antitumoral effects through apoptosis induction and inhibition of glioblastoma angiogenesis.

The goal of this study was to discuss cannabinoid therapy and also what cellular mechanisms are involved in the tumoricidal effect of the cannabinoids.

In this review article, we will focus on cannabinoids, their receptor dependent functional roles against glioblastoma acccording to growth, angiogenesis, metastasis, and future purposes in exploring new possible therapeutic opportunities.”

http://journals.sbmu.ac.ir/Neuroscience/article/view/13655