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Cannabigerol Is a Potential Therapeutic Agent in a Novel Combined Therapy for Glioblastoma

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Among primary brain tumours, glioblastoma is the most aggressive. As early relapses are unavoidable despite standard-of-care treatment, the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone or in combination have been suggested as a combined treatment strategy for glioblastomas. However, the known psychoactive effects of THC hamper its medical applications in these patients with potential cognitive impairment due to the progression of the disease. Therefore, nontoxic cannabigerol (CBG), being recently shown to exhibit anti-tumour properties in some carcinomas, is assayed here for the first time in glioblastoma with the aim to replace THC. We indeed found CBG to effectively impair the relevant hallmarks of glioblastoma progression, with comparable killing effects to THC and in addition inhibiting the invasion of glioblastoma cells. Moreover, CBG can destroy therapy-resistant glioblastoma stem cells, which are the root of cancer development and extremely resistant to various other treatments of this lethal cancer. CBG should present a new yet unexplored adjuvant treatment strategy of glioblastoma.

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Cannabidiol (CBD) inhibits glioblastoma progression through regulation of tumor microenvironment in a murine model

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Glioblastoma multiforme (GBM) is the most common invasive brain tumor composed of diverse cell types with poor prognosis. The highly complex tumor microenvironment (TME) and its interaction with tumor cells play important roles in the development, progression, and durability of GBM. Angiogenic and immune factors are two major components of TME of GBM, their interplay is a major determinant of tumor vascularization, immune profile, as well as immune unresponsiveness of GBM. Given the ineffectiveness of current standard therapies (surgery, radiotherapy, and concomitant chemotherapy) in managing patients with GBM, it is necessary to develop new ways of treating these lethal brain tumors. Targeting TME, altering tumor ecosystem may be a viable therapeutic strategy with beneficial effects for patients in their fight against GBM.

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Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities

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Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds.

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Cannabidiol Treatment Results in a Common Gene Expression Response Across Aggressive Cancer Cells from Various Origins

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Glioblastoma multiforme (GBM) is a relatively rare type of brain tumour with an incidence rate around 6 per 100,000. Even with the widely practiced combination of radiotherapy with adjuvant temozolomide, the median overall survival remains low with just 13.5 to 16 months after diagnosis. Patients and Methods: We retrospectively reviewed the survival of a cohort of 15 consecutive, unselected patients with histopathologically confirmed glioblastoma multiforme (GBM) who received CBD (400 to 600 mg orally per day) in addition to standard therapy (maximum resection of the tumour followed by radio- chemotherapy). Results: Of 15 patients, seven (46.7%) are now living for at least 24 months, and four (26.7%) for at least 36 months. This is more than twice as long as has been previously reported in the literature. The mean overall survival is currently 24.2 months (median 21 months). Conclusion: CBD is a well supported co-medication and seems to prolong the survival of patients with glioblastoma multiforme.

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Concomitant Treatment of Malignant Brain Tumours With CBD – A Case Series and Review of the Literature.

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Authors: Rudolf Likar, Markus Koestenberger, Martin Stultschnig, Gerhard Nahler
Anticancer Research, October 2019
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Grade IV glioblastoma multiforme is a deadly disease, with a median survival of around 14 to 16 months. Maximal resection followed by adjuvant radiochemotherapy has been the mainstay of treatment since many years, although survival is only extended by a few months. In recent y…

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Current natural therapies in the treatment against glioblastoma.

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Authors: José Ignacio Erices, Ángelo Torres, Ignacio Niechi, Isabel Bernales, Claudia Quezada
Phytotherapy Research, November 2018
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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, in…

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A Safety Study of Sativex in Combination With Dose-intense Temozolomide in Patients With Recurrent Glioblastoma

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Authors: Susan Short, Christopher Twelves, Lucy Brazil, Catherine McBain, et al
Clinicaltrials.gov, 11 August 2016
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An open-label phase to assess the frequency and severity of adverse events in recurrent glioblastoma patients receiving Sativex in combination with dose-intense Temozolomide (Part A). A randomisation phase to assess the safety of Sativex compared with placebo (Part B). Patient…

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Targeting endocannabinoid signaling in tumor‐associated macrophages as treatment for glioblastoma multiforme

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Authors: Susan Fung, Nephi Stella
Wiley Interdisciplinary Reviews: Membrane Transport and Signaling, 21 January 2014
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Glioblastoma multiforme (GBM) is the most common form of primary brain tumor and is diagnosed in approximately 15,000 people each year in the United States alone. No cure for this type of cancer exists, and the current standard of care treatments provide little benefit and are…

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A combined preclinical therapy of cannabinoids and temozolomide against glioma.

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Authors: Sofía Torres, Mar Lorente, Fátima Rodríguez-Fornés, Sonia Hernández-Tiedra, et al
Molecular Cancer Therapeutics, January 2011
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Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ(9)-Tetrahydrocannabinol (THC), the major active ingred…

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Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival.

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Authors: Jahan P. Marcu, Rigel T. Christian, Darryl Lau, Anne J. Zielinski, Maxx P. Horowitz, et al
Molecular Cancer Therapeutics, January 2010
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The cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor agonist Delta(9)-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has bee…

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A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.

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Authors: M. Guzmán, M. J. Duarte, C. Blázquez, J. Ravina, M. C. Rosa, I. Galve-Roperh, et al
British Journal of Cancer, 17 July 2006
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Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we…

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