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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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Endocannabinoid signaling in glioma

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High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB1 and CB2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling path- ways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvi- ronment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.

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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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Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas–possible role of Cannabis inhalation.

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Authors: Mansoor Foroughi, Glenda Hendson, Michael A. Sargent, Paul Steinbok
Child’s Nervous System, DATE
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INTRODUCTION: Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous reg…

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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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Cannabinoid receptors in human astroglial tumors.

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Authors: Janka Held‐Feindt, Lutz Dörner, Gülcan Sahan,H. Maximilian Mehdorn, Rolf Mentlein
Journal of Neurochemistry, August 2008
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In animal models, cannabinoids are reported to inhibit the growth of tumors, including gliomas. These effects have been claimed to be mediated via cannabinoid receptors 1 and 2 (CB1, CB2). To elucidate a possible relevance for treatment of human gliomas, we investigated recept…

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Cannabinoids for cancer treatment: progress and promise.

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Authors: Sami Sarfaraz, Vaqar M. Adhami, Deeba N. Syed, Farrukh Afaq, Hasan Mukhtar
Cancer Research, 15 January 2008
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Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of…

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Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism.

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Authors: Angelo Vaccani, Paola Massi, Arianna Colombo, Tiziana Rubino, Daniela Parolaro
British Journal of Pharmacology, April 2005
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We evaluated the ability of cannabidiol (CBD) to impair the migration of tumor cells stimulated by conditioned medium. CBD caused concentration-dependent inhibition of the migration of U87 glioma cells, quantified in a Boyden chamber. Since these cells express both cannabinoid…

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