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

cells-logo“Glioblastoma is the most aggressive cancer among primary brain tumours. As with other cancers, the incidence of glioblastoma is increasing; despite modern therapies, the overall mean survival of patients post-diagnosis averages around 16 months, a figure that has not changed in many years. Cannabigerol (CBG) has only recently been reported to prevent the progression of certain carcinomas and has not yet been studied in glioblastoma. Here, we have compared the cytotoxic, apoptotic, and anti-invasive effects of the purified natural cannabinoid CBG together with CBD and THC on established differentiated glioblastoma tumour cells and glioblastoma stem cells. CBG and THC reduced the viability of both types of cells to a similar extent, whereas combining CBD with CBG was more efficient than with THC. CBD and CBG, both alone and in combination, induced caspase-dependent cell apoptosis, and there was no additive THC effect. Of note, CBG inhibited glioblastoma invasion in a similar manner to CBD and the chemotherapeutic temozolomide. We have demonstrated that THC has little added value in combined-cannabinoid glioblastoma treatment, suggesting that this psychotropic cannabinoid should be replaced with CBG in future clinical studies of glioblastoma therapy.”

https://pubmed.ncbi.nlm.nih.gov/33562819/

“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.”

https://www.mdpi.com/2073-4409/10/2/340

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THE PHARMACOLOGICAL CASE FOR CANNABIGEROL (CBG)

Journal of Pharmacology and Experimental Therapeutics: 375 (3) “Medical cannabis and individual cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), are receiving growing attention in both the media and the scientific literature. The Cannabis plant, however, produces over 100 different cannabinoids, and cannabigerol (CBG) serves as the precursor molecule for the most abundant phytocannabinoids.

CBG exhibits affinity and activity characteristics between THC and CBD at the cannabinoid receptors, but appears to be unique in its interactions with alpha-2 adrenoceptors and 5-HT1A Studies indicate that CBG may have therapeutic potential in treating neurological disorders (e.g., Huntington’s Disease, Parkinson’s Disease, and multiple sclerosis), inflammatory bowel disease, as well as having antibacterial activity.

There is growing interest in the commercial use of this unregulated phytocannabinoid. This review focuses on the unique pharmacology of CBG, our current knowledge of its possible therapeutic utility, and its potential toxicological hazards.

Significance Statement Cannabigerol (CBG) is currently being marketed as a dietary supplement and, as with cannabidiol (CBD) before, many claims are being made about its benefits. Unlike CBD, however, little research has been performed on this unregulated molecule, and much of what is known warrants further investigation to identify potential areas of therapeutic uses and hazards.”

https://pubmed.ncbi.nlm.nih.gov/33168643/

https://jpet.aspetjournals.org/content/early/2020/11/09/jpet.120.000340

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Cannabinoid Combination Induces Cytoplasmic Vacuolation in MCF-7 Breast Cancer Cells

molecules-logo“This study evaluated the synergistic anti-cancer potential of cannabinoid combinations across the MDA-MB-231 and MCF-7 human breast cancer cell lines. Cannabinoids were combined and their synergistic interactions were evaluated using median effect analysis.

The most promising cannabinoid combination (C6) consisted of tetrahydrocannabinol, cannabigerol (CBG), cannabinol (CBN), and cannabidiol (CBD), and displayed favorable dose reduction indices and limited cytotoxicity against the non-cancerous breast cell line, MCF-10A. C6 exerted its effects in the MCF-7 cell line by inducing cell cycle arrest in the G2 phase, followed by the induction of apoptosis.

Morphological observations indicated the induction of cytoplasmic vacuolation, with further investigation suggesting that the vacuole membrane was derived from the endoplasmic reticulum. In addition, lipid accumulation, increased lysosome size, and significant increases in the endoplasmic reticulum chaperone protein glucose-regulated protein 78 (GRP78) expression were also observed.

The selectivity and ability of cannabinoids to halt cancer cell proliferation via pathways resembling apoptosis, autophagy, and paraptosis shows promise for cannabinoid use in standardized breast cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/33066359/

https://www.mdpi.com/1420-3049/25/20/4682

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Efficacy of combined therapy with fish oil and phytocannabinoids in murine intestinal inflammation

Phytotherapy Research“Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects.

We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately.

Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability.

CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon.

By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.”

https://pubmed.ncbi.nlm.nih.gov/32996187/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.6831

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A Comparative In Vitro Study of the Neuroprotective Effect Induced by Cannabidiol, Cannabigerol, and Their Respective Acid Forms: Relevance of the 5-HT 1A Receptors

 SpringerLink“Previous preclinical studies have demonstrated that cannabidiol (CBD) and cannabigerol (CBG), two non-psychotomimetic phytocannabinoids from Cannabis sativa, induce neuroprotective effects on toxic and neurodegenerative processes.

Our results contribute to the understanding of the neuroprotective effect of CBD and CBG, showing differences with their acid forms, and also highlight the role of 5-HT1A receptors in the mechanisms of action of CBG.”

https://pubmed.ncbi.nlm.nih.gov/32886342/

https://link.springer.com/article/10.1007%2Fs12640-020-00277-y

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Pharmacological Data of Cannabidiol- And Cannabigerol-Type Phytocannabinoids Acting on Cannabinoid CB 1, CB 2 and CB 1/CB 2 Heteromer Receptors

Pharmacological Research“Background: Recent approved medicines whose active principles are Δ9Tetrahidrocannabinol (Δ9-THC) and/or cannabidiol (CBD) open novel perspectives for other phytocannabinoids also present in Cannabis sativa L. varieties. Furthermore, solid data on the potential benefits of acidic and varinic phytocannabinoids in a variety of diseases are already available. Mode of action of cannabigerol (CBG), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarin (CBDV) and cannabigerivarin (CBGV) is, to the very least, partial.

Hypothesis/purpose: Cannabinoid CB1 or CB2 receptors, which belong to the G-protein-coupled receptor (GPCR) family, are important mediators of the action of those cannabinoids. Pure CBG, CBDA, CBGA, CBDV and CBGV from Cannabis sativa L. are differentially acting on CB1 or CB2 cannabinoid receptors.

Study design: Determination of the affinity of phytocannabinoids for cannabinoid receptors and functional assessment of effects promoted by these compounds when interacting with cannabinoid receptors.

Methods: A heterologous system expressing the human versions of CB1 and/or CB2 receptors was used. Binding to membranes was measured using radioligands and binding to living cells using a homogenous time resolved fluorescence resonance energy transfer (HTRF) assay. Four different functional outputs were assayed: determination of cAMP levels and of extracellular-signal-related-kinase phosphorylation, label-free dynamic mass redistribution (DMR) and ß-arrestin recruitment.

Results: Affinity of cannabinoids depend on the ligand of reference and may be different in membranes and in living cells. All tested phytocannabinoids have agonist-like behavior but behaved as inverse-agonists in the presence of selective receptor agonists. CBGV displayed enhanced potency in many of the functional outputs. However the most interesting result was a biased signaling that correlated with differential affinity, i.e. the overall results suggest that the binding mode of each ligand leads to specific receptor conformations underlying biased signaling outputs.

Conclusion: Results here reported and the recent elucidation of the three-dimensional structure of CB1 and CB2 receptors help understanding the mechanism of action that might be protective and the molecular drug-receptor interactions underlying biased signaling.”

https://pubmed.ncbi.nlm.nih.gov/32470563/

https://www.sciencedirect.com/science/article/abs/pii/S1043661820312482?via%3Dihub

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Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

ijms-logo“Cannabidiol (CBD) and cannabigerol (CBG) are Cannabis sativa terpenophenols.

Although CBD’s effectiveness against neurological diseases has already been demonstrated, nothing is known about CBG. Therefore, a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases.

Rat astrocytes were exposed to hydrogen peroxide and cell viability, reactive oxygen species production and apoptosis occurrence were investigated. Cortexes were exposed to K+ 60 mM depolarizing stimulus and serotonin (5-HT) turnover, 3-hydroxykinurenine and kynurenic acid levels were measured. A proteomic analysis and bioinformatics and docking studies were performed.

Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli, whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid. CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis. Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor.

Conclusion: The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions, whereas findings in the ex vivo system and docking analyses imply the potential roles of CBD and CBG as neuroprotective agents.”

https://pubmed.ncbi.nlm.nih.gov/32443623/

https://www.mdpi.com/1422-0067/21/10/3575

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Cannabidiol (CBD).

Cover of StatPearls“Cannabis sativa or Indian hemp (subfamily Cannaboideae of family Moraceae) is an annual herbaceous plant, native to central and western Asia, cultivated for medicinal properties and for hemp, which is a natural textile fiber. The plant contains over 400 chemical compounds, of which approximately 80 biologically active chemical molecules. The most important cannabis compounds are cannabinoids formed by a terpene combined with resorcinol, or, according to a different nomenclature, by a benzopyranic ring system. There are about sixty cannabinoids, of which the most important psychoactive compound is tetrahydrocannabinol (TCH), in particular the isomer delta (Δ9-THC). Other identified compounds are cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and olivetol. In addition to cannabinoids, the plant contains terpenoids such as beta-myrcene, beta-caryophyllene, d-limonene, linalool, piperidine, and p-cymene, as well as flavonoids such as quercetin.”

https://www.ncbi.nlm.nih.gov/pubmed/32310508

https://www.ncbi.nlm.nih.gov/books/NBK556048/

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Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.

Biochemical Pharmacology“The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes.

In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on the viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes.

We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and CBD (5 µM) alone or in their combination promote their maturation into adipocytes via distinct molecular mechanisms. These effects were revealed both in vitro and in vivo. In addition, phytocannabinoids prevented the insulin signalling impairment induced by palmitate in adipocytes differentiated from BM-MSCs.

Our study highlights phytocannabinoids as a potential novel pharmacological tool to regain control of functional adipose tissue in unregulated energy homeostasis often occurring in metabolic disorders including type 2 diabetes mellitus (T2DM), aging and lipodystrophy.”

https://www.ncbi.nlm.nih.gov/pubmed/32061773

“The promiscuous pharmacology of phytocannabinoids makes them viable candidates for new medicines for the treatment of metabolic syndromes through the simultaneous resolution of collective complications due to impaired development, maintenance, activity and function of the adipose tissue. Furthermore, phytocannabinoids are generally well tolerated in comparison to potent synthetic PPAR agonists, and combination treatments may further improve their efficacy at lower doses.”

https://www.sciencedirect.com/science/article/pii/S0006295220300873?via%3Dihub

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Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus.

antioxidants-logo “Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed.

RESULTS:

Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis.

CONCLUSION:

The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31941059

https://www.mdpi.com/2076-3921/9/1/71

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