Tag: cannabidiol

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Inhalant Cannabidiol Inhibits Glioblastoma Progression Through Regulation of Tumor Microenvironment

Abstract

Introduction: Glioblastoma (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.

Materials and Methods: Given the potential therapeutic effects of cannabidiol (CBD) in a wide spectrum of diseases, including malignancies, we tested, for the first time, whether inhalant CBD can inhibit GBM tumor growth using a well-established orthotopic murine model. Optical imaging, histology, immunohistochemistry, and flow cytometry were employed to describe the outcomes such as tumor progression, cancer cell signaling pathways, and the TME.

Results: Our findings showed that inhalation of CBD was able to not only limit the tumor growth but also to alter the dynamics of TME by repressing P-selectin, apelin, and interleukin (IL)-8, as well as blocking a key immune checkpoint—indoleamine 2,3-dioxygenase (IDO). In addition, CBD enhanced the cluster of differentiation (CD) 103 expression, indicating improved antigen presentation, promoted CD8 immune responses, and reduced innate Lymphoid Cells within the tumor.

Conclusion: Overall, our novel findings support the possible therapeutic role of inhaled CBD as an effective, relatively safe, and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME, warranting further research.

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Cannabidiol suppresses 3-dimensional ovarian cancer growth and may enhance potency of classic and epigenetic therapies

Over an extended kinetic, high and medium concentrations of one time CBD (CBDH) tended to stunt spheroid growth in comparison to control, (686% and over 700% less growth). Low concentrations of one time CBD (CBDL) had a lessened effect on spheroid growth, (556% less growth). Classic chemotherapy combined with CBD contributed to a decreased overall spheroid growth, and even shrinkage with one time CBDL (34% shrinkage versus 84% growth in C/T group) over an extended kinetic. Chronic CBDH administration resulted in greater than 7500% less growth by day 10. Chronic CBDL in combination with C/T resulted in a 99% less growth in comparison to C/T by day 6. One time CBD administration with Panobinostat (Pano) decreased the amount of growth over a shorter kinetic (18% and 2% shrinkage for Pano/CBDL and Pano/CBDM, respectively, versus 13% growth for Pano). With the application of chronic CBD, Pano and CBD resulted in shrinkage early on and even 100% lysis of 3D OC by day 10.

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

Abstract

Background: We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity profile, downregulated the expression of the prometastatic gene inhibitor of DNA binding 1 (ID1) in cancer cells, leading to inhibition of tumor progression in vivo. While CBD is broadly used, including in the self-medication of cancer patients, and CBD-based therapies are undergoing clinical evaluation for cancer treatment, its mechanisms of action are still poorly understood.

Methods: In this study, using microarray analysis and Western blot analysis for validation, we attempted to identify the full spectrum of genes regulated by CBD across various aggressive cancer cell lines, including the breast, brain, head and neck, and prostate.

Results: We confirmed that ID1 was a major target downregulated by CBD and also discovered that CBD inhibited FOXM1 (Forkhead box M1), a transcriptional activator involved in cell proliferation, while simultaneously upregulating GDF15 (growth differentiation factor 15), a cytokine associated with tissue differentiation.

Conclusion: Our results suggest that, by modulating expression of shared key cancer-driving genes, CBD could represent a promising nontoxic therapeutic for treating tumors of various origins.

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Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma

Abstract

Cannabidiol (CBD) has anti-tumorigenic activity. However, the anti-cancer effect of CBD on head and neck squamous cell carcinoma (HNSCC) remains unclear. The cytotoxicity of CBD on HNSCC was analyzed using cell survival and colony-forming assays in vitro. RNA-seq was used for determining the mechanism underlying CBD-induced cell death. Xenograft mouse models were used to determine CBD’s effects in vivo. CBD treatment significantly reduced migration/invasion and viability of HNSCC cells in a dose- and time-dependent manner. HNSCC mouse xenograft models revealed anti-tumor effects of CBD. Furthermore, combinational treatment with CBD enhanced the efficacy of chemotherapy drugs. Apoptosis and autophagy processes were involved in CBD-induced cytotoxicity of HNSCCs. RNA-seq identified decreased expression of genes associated with DNA repair, cell division, and cell proliferation, which were involved in CBD-mediated cytotoxicity toward HNSCCs. We identified CBD as a new potential anti-cancer compound for single or combination therapy of HNSCC.

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CBD as a Promising Anti-Cancer Drug

Abstract

Recently, cannabinoids, such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), have been the subject of intensive research and heavy scrutiny. Cannabinoids encompass a wide array of organic molecules, including those that are physiologically produced in humans, synthesized in laboratories, and extracted primarily from the Cannabis sativa plant. These organic molecules share similarities in their chemical structures as well as in their protein binding profiles. However, pronounced differences do exist in their mechanisms of action and clinical applications, which will be briefly compared and contrasted in this review. The mechanism of action of CBD and its potential applications in cancer therapy will be the major focus of this review article.

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Enhancing ovarian cancer conventional chemotherapy through the combination with cannabidiol loaded microparticles

In this work, we evaluated, for the first time, the antitumor effect of cannabidiol (CBD) as monotherapy and in combination with conventional chemotherapeutics in ovarian cancer and developed PLGA-microparticles as CBD carriers to optimize its anticancer activity. Spherical microparticles, with a mean particle size around 25 µm and high entrapment efficiency were obtained. Microparticles elaborated with a CBD:polymer ratio of 10:100 were selected due to the most suitable release profile with a zero-order CBD release (14.13 ± 0.17 μg/day/10 mg Mps) for 40 days. The single administration of this formulation showed an in vitro extended antitumor activity for at least 10 days and an in ovo antitumor efficacy comparable to that of CBD in solution after daily topical administration (≈1.5-fold reduction in tumor growth vs control). The use of CBD in combination with paclitaxel (PTX) was really effective. The best treatment schedule was the pre + co-administration of CBD (10 µM) with PTX. Using this protocol, the single administration of microparticles was even more effective than the daily administration of CBD in solution, achieving a ≈10- and 8- fold reduction in PTX IC50 respectively. This protocol was also effective in ovo. While PTX conducted to a 1.5-fold tumor growth inhibition, its combination with both CBD in solution (daily administered) and 10-Mps (single administration) showed a 2-fold decrease. These results show the promising potential of CBD-Mps administered in combination with PTX for ovarian cancer treatment, since it would allow to reduce the administered dose of this antineoplastic drug maintaining the same efficacy and, as a consequence, reducing PTX adverse effects.

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Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4

Abstract

Glioma is the most common primary malignant brain tumor with poor survival and limited therapeutic options. The non-psychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against glioma; however, the molecular target and mechanism of action of CBD in glioma are poorly understood. Here we investigated the molecular mechanisms underlying the antitumor effect of CBD in preclinical models of human glioma. Our results showed that CBD induced autophagic rather than apoptotic cell death in glioma cells. We also showed that CBD induced mitochondrial dysfunction and lethal mitophagy arrest, leading to autophagic cell death. Mechanistically, calcium flux induced by CBD through TRPV4 (transient receptor potential cation channel subfamily V member 4) activation played a key role in mitophagy initiation. We further confirmed TRPV4 levels correlated with both tumor grade and poor survival in glioma patients. Transcriptome analysis and other results demonstrated that ER stress and the ATF4-DDIT3-TRIB3-AKT-MTOR axis downstream of TRPV4 were involved in CBD-induced mitophagy in glioma cells. Lastly, CBD and temozolomide combination therapy in patient-derived neurosphere cultures and mouse orthotopic models showed significant synergistic effect in both controlling tumor size and improving survival. Altogether, these findings showed for the first time that the antitumor effect of CBD in glioma is caused by lethal mitophagy and identified TRPV4 as a molecular target and potential biomarker of CBD in glioma. Given the low toxicity and high tolerability of CBD, we therefore propose CBD should be tested clinically for glioma, both alone and in combination with temozolomide.

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The potential of cannabidiol in the COVID-19 pandemic

Identifying candidate drugs effective in the new coronavirus disease 2019 (Covid‐19) is crucial, pending a vaccine against SARS‐CoV2. We suggest the hypothesis that Cannabidiol (CBD), a non‐psychotropic phytocannabinoid, has the potential to limit the severity and progression of the disease for several reasons: 1) High‐CBD Cannabis Sativa extracts are able to downregulate the expression of the two key receptors for SARS‐CoV2 in several models of human epithelia 2) CBD exerts a wide range of immunomodulatory and anti‐inflammatory effects and it can mitigate the uncontrolled cytokine production featuring Acute Lung Injury 3) Being a PPARγ agonist, it can display a direct antiviral activity 4) PPARγ agonists are regulators of fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our hypothesis, corroborated by several preclinical evidence, will inspire further targeted studies to test CBD as a support drug against the COVID‐19 pandemic.

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Fighting the storm: novel anti- TNFα and anti-IL-6 C. sativa lines to tame cytokine storm in COVID-19

Overall, we are the first to show that application of C. sativa extracts profoundly decreases the level of pro-inflammatory cytokines in human 3D tissues. Still, our study has several pitfalls. Here, we used human 3D full-thickness skin model to analyze the effects of cannabis extracts on inflammation and fibrosis. While it would be important to replicate the data in an airway epithelial and alveolar tissue models, our data can be used as a roadmap for the future analysis. Moreover, key fundamental mechanisms of inflammation and fibrosis are similar in various tissues, and key roles of TNFα, IL-6 and other interleukins, chemokines, and MMPS have been well-established in an array of fibroproliferative diseases15. Pending further validation in lung tissue models, our novel extracts need to be studied in a clinical trial aimed to prevent or mitigate COVID-19 pneumonia and ARDS. To do so, the extracts have to be administered early upon positive diagnosis has been made to allow sufficient time for modulation of cytokine levels.

Most importantly, out of 7 selected extracts, only 3 performed best, one had no effects at all, and one exerted effects that may in turn be deleterious, signifying that cannabis is not generic and cultivar selection must be based on thorough pre-clinical studies. Furthermore, the current study was developed to analyze the effects of medical cannabis applications rather than smoking.

In the future, anti-TNFα and anti-IL-6 extracts need to be analyzed for their potential to mitigate inflammation in rheumatoid arthritis, ankylosing spondylitis, and other rheumatologic conditions, especially given the fact that extracts profoundly downregulate the RA pathway and target TNFα and IL-6. Also, the effects of novel extracts also need to be analyzed for their potential to combat ‘inflammaging’ – the inflammatory underpinning of aging and frailty.

Anna Kovalchuk, Rocio Rodriguez-Juarez, Slava Ilnytskyy, Dongping Li, Bo Wang, Igor Kovalchuk, Olga Kovalchuk Published 2020 May 22. 

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