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

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.”

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Cannabinoids in cancer treatment: Therapeutic potential and legislation.

Bosnian Journal of Basic Medical Sciences

“The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids.

The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes.

Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer.

In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite.

In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types.

Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries.

In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration.

Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients.

The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.”

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Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer.

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“Exosomes and microvesicles (EMV) are lipid bilayer-enclosed structures, released by cells and involved in intercellular communication through transfer of proteins and genetic material. EMV release is also associated with various pathologies, including cancer, where increased EMV release is amongst other associated with chemo-resistance and active transfer of pro-oncogenic factors.

Recent studies show that EMV-inhibiting agents can sensitize cancer cells to chemotherapeutic agents and reduce cancer growth in vivo.

Cannabidiol (CBD), a phytocannabinoid derived from Cannabis sativa, has anti-inflammatory and anti-oxidant properties, and displays anti-proliferative activity.

Here we report a novel role for CBD as a potent inhibitor of EMV release from three cancer cell lines: prostate cancer (PC3), hepatocellular carcinoma (HEPG2) and breast adenocarcinoma (MDA-MB-231).

CBD significantly reduced exosome release in all three cancer cell lines, and also significantly, albeit more variably, inhibited microvesicle release.

The EMV modulating effects of CBD were found to be dose dependent (1 and 5 μM) and cancer cell type specific. Moreover, we provide evidence that this may be associated with changes in mitochondrial function, including modulation of STAT3 and prohibitin expression, and that CBD can be used to sensitize cancer cells to chemotherapy.

We suggest that the known anti-cancer effects of CBD may partly be due to the regulatory effects on EMV biogenesis, and thus CBD poses as a novel and safe modulator of EMV-mediated pathological events.”

https://www.ncbi.nlm.nih.gov/pubmed/30150937

https://www.frontiersin.org/articles/10.3389/fphar.2018.00889/full

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

 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

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Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus.

European Journal of Medicinal Chemistry

“Cannabaceae plants Cannabis sativa L. and Humulus lupulus L. are rich in terpenes – both are typically comprised of terpenes as up to 3-5% of the dry-mass of the female inflorescence.

Terpenes of cannabis and hops are typically simple mono- and sesquiterpenes derived from two and three isoprene units, respectively. Some terpenes are relatively well known for their potential in biomedicine and have been used in traditional medicine for centuries, while others are yet to be studied in detail.

The current, comprehensive review presents terpenes found in cannabis and hops. Terpenes’ medicinal properties are supported by numerous in vitro, animal and clinical trials and show anti-inflammatory, antioxidant, analgesic, anticonvulsive, antidepressant, anxiolytic, anticancer, antitumor, neuroprotective, anti-mutagenic, anti-allergic, antibiotic and anti-diabetic attributes, among others.

Because of the very low toxicity, these terpenes are already widely used as food additives and in cosmetic products. Thus, they have been proven safe and well-tolerated.”

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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/
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Cannabis: A Prehistoric Remedy for the Deficits of Existing and Emerging Anticancer Therapies

“Cannabis has been used medicinally for centuries and numerous species of this genus are undoubtedly amongst the primeval plant remedies known to humans.

Cannabis sativa in particular is the most reported species, due to its substantial therapeutic implications that are owed to the presence of chemically and pharmacologically diverse cannabinoids.

These compounds have long been used for the palliative treatment of cancer.

Recent advancements in receptor pharmacology research have led to the identification of cannabinoids as effective antitumor agents.

This property is accredited for their ability to induce apoptosis, suppress proliferative cell signalling pathways and promote cell growth inhibition.

Evolving lines of evidence suggest that cannabinoid analogues, as well as their receptor agonists, may offer a novel strategy to treat various forms of cancer.

This review summarizes the historical perspective of C. sativa, its potential mechanism of action, and pharmacokinetic and pharmacodynamic aspects of cannabinoids, with special emphasis on their anticancer potentials.”

http://www.xiahepublishing.com/ArticleFullText.aspx?sid=2&jid=3&id=10.14218%2FJERP.2017.00012

Cannabis products.

“Cannabis products. First row, left to right: Indian, Lebanese, Turkish and Pakistani hashish. Second row, left to right: Swiss hashish, Zairean marijuana, Swiss marijuana, Moroccan hash oil.”

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The importance of 15-lipoxygenase inhibitors in cancer treatment.

Cancer and Metastasis Reviews

“Cancer-targeted therapy is an expanding and successful approach in treatment of many types of cancers. One of the main categories of targeted therapy is use of small molecule inhibitors. 15-Lipoxygenase (15-LOX) is an enzyme which reacts with polyunsaturated fatty acids and produces metabolites that are implicated in many important human diseases, such as cancer.

Considering the role of 15-LOX (mainly 15-LOX-1) in the progression of some cancers, the discovery of 15-LOX inhibitors could potentially lead to development of novel cancer therapeutics and it can be claimed that 15-LOX inhibitors might be suitable as chemotherapy agents in the near future.

This article reviews relevant publications on 15-LOX inhibitors with focus on their anticancer activities in vitro and in vivo. Many 15-LOX inhibitors have been reported for which separate studies have shown their anticancer activities. This review paves the way to further explore the mechanism of their antiproliferative effects via 15-LOX inhibition.”

“Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor”  http://dmd.aspetjournals.org/content/37/8/1733.long

“Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors.”  https://www.ncbi.nlm.nih.gov/pubmed/20891010

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Novel therapeutic applications of cannabinoids in cancer disease

oatext

“The present review shows that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

The endocannabinoid system is an almost ubiquitous signalling system involved in the control of cell fate. Recent studies have investigated the possibility that drugs targeting the endocannabinoid system might be used to retard or block cancer growth.

The endocannabinoids have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell signalling pathways. Therefore, the present review indicated that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumours
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighbouring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

Furthermore, the novel therapeutic application of cannabinoids in cancer disease, described here, strongly support the idea that cannabinoids may induce benefical effect in cancer treatment.”

http://www.oatext.com/novel-therapeutic-applications-of-cannabinoids-in-cancer-disease.php

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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.”
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