Tag: cbd

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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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Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment?

In murine models of lung injury, CBD reduced lipopolysaccharide (LPS)-induced acute pulmonary inflammation [41,42]. In rat models of experimental asthma, CBD treatment reduced airway inflammation, as well as levels of serum IL-4, IL-5, IL-13, IL-6 and TNF-α, which are implicated in airway inflammation and fibrosis in asthma [43,44]. Moreover, CBD was able to directly suppress T-cell secretion of IL-1 and IFNγ [45]. In piglets with hypoxic-ischemic lung damage, CBD reduced histologic damage, decreased leukocyte infiltration and modulated IL-1 concentration in bronchoalveolar lavage fluid [46], while in a rat model of sepsis, CBD reversed oxidative stress and reduced mortality [47]. In humans, cannabinoid use prevented induction of pro-inflammatory CD16+ monocytes and production of IP-10, In murine models of lung injury, CBD reduced lipopolysaccharide (LPS)-induced acute pulmonary inflammation [41,42]. In rat models of experimental asthma, CBD treatment reduced airway inflammation, as well as levels of serum IL-4, IL-5, IL-13, IL-6 and TNF-α, which are implicated in airway inflammation and fibrosis in asthma [43,44]. Moreover, CBD was able to directly suppress T-cell secretion of IL-1 and IFNγ [45]. In piglets with hypoxic-ischemic lung damage, CBD reduced histologic damage, decreased leukocyte infiltration and modulated IL-1 concentration in bronchoalveolar lavage fluid [46], while in a rat model of sepsis, CBD reversed oxidative stress and reduced mortality [47]. In humans, cannabinoid use prevented induction of pro-inflammatory CD16+ monocytes and production of IP-10, suggesting anti-inflammatory effects in humans [48]. In another human study, in addition to reduction of pro-inflammatory monocytes, heavy cannabis use was also associated with decreased frequencies of HLA-DR+CD38+ activated CD4 and CD8 T-cells and frequencies of IL-10, IL-12 and TNF-α -producing antigen presenting cells compared to non-cannabis users [49].

Cecilia T. Costiniuk and Mohammad-Ali Jenabian Published online 2020 May 20. doi:10.1016/j.cytogfr.2020.05.008

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SARS-CoV2 induced respiratory distress: Can cannabinoids be added to anti-viral therapies to reduce lung inflammation?

Like Δ9-tetrahydrocannabinol (Δ9-THC), the most well-studied cannabinoid, CBD decreased lung inflammation in a murine model of acute lung injury potentially through the inhibition of proinflammatory cytokine production by immune cells and suppressing exuberant immune responses (Ribeiro et al., 2015). CBD can inhibit the production of proinflammatory cytokines like interleukin (IL)-2, IL-6, IL-1α and β, interferon gamma, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α (Nichols and Kaplan, 2020) (Fig. 1 ) that have been associated with SARS-CoV2 induced multi-organ pathology and mortality. In a murine model of chronic asthma, CBD reduced proinflammatory cytokine production, airway inflammation and fibrosis (Vuolo et al., 2019). Moreover, CBD can effectively inhibit the JAK-STAT pathway including the production and action of type I interferons without leading to addiction, alterations in heart rate or blood pressure and adverse effects on the gastrointestinal tract and cognition (Nichols and Kaplan, 2020). In simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), we reported THC mediated attenuation of IFN stimulated gene expression in the intestine (Kumar et al., 2019). Similar to CBD, chronic THC administration blocked inflammation induced fibrosis in lymph nodes of chronically SIV-infected RMs (Kumar et al., 2019). Unlike THC, CBD has a high margin of safety and is well tolerated pharmacologically even after treatments of up to 1500 mg/day for two weeks in both animals and humans (Nichols and Kaplan, 2020), which suggests its feasibility to reduce SARS-CoV2 induced lung inflammation/pathology and disease severity.

Siddappa N Byrareddy and Mahesh Mohan Published online 2020 Apr 28. doi:10.1016/j.bbi.2020.04.079

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In Search of Preventative Strategies: Novel Anti-Inflammatory High-CBD Cannabis Sativa Extracts Modulate ACE2 Expression in COVID-19 Gateway Tissues

The observed down-regulation of ACE2 gene expression by several tested extracts of C. sativa is a novel and crucial finding. Our results lay a foundation for further in-depth analysis of the effects of C. sativa on the molecular etiology and pathogenesis of COVID-19, as well as other viral diseases in which viruses use the ACE2 receptor as a molecular gateway. If further confirmed, select high-CBD cannabis extracts can be used to develop prevention strategies directed at lowering or modulating ACE2 levels in high-risk tissues. ACE2 level modulation is of particular importance since it appears to change throughout disease progression, and some studies show that ACE2 is essential for lung function in animal models of SARS. It would also be important to test the effects of C. sativa lines on other receptors involved in SARS-CoV2 entry, as well as for their anti-inflammatory potential.

Bo Wang, Anna Kovalchuk, Dongping Li, Yaroslav Ilnytskyy, Igor Kovalchuck and Olga Kovalchuck Published online 2020 Apr 19. 
doi:10.20944/preprints202004.0315.v1

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Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

Abstract

Radiotherapy combined with chemotherapy is the major treatment modality for human glioblastoma multiforme (GBM). GBMs eventually relapse after treatment and the average survival of GBM patients is less than two years. There is some evidence that cannabidiol (CBD) can induce cell death and increases the radiosensitivity of GBM by enhancing apoptosis. Beside initiation of death, CBD has been demonstrated as an inducer of autophagy. In the present study, we address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy. Addition of chloroquine that suppressed autophagic flux to 2D GBM cultures increased CBD-induced cell death, presenting proof for the protective autophagy. Blockage of autophagy upregulated radiation-induced cytotoxicity but only modestly affected the levels of cell death in CBD- or CBD/γ-irradiated 3D GBM cultures. Furthermore, CBD enhanced the pro-apoptotic activities of JNK1/2 and MAPK p38 signaling cascades while partially downregulated the pro-survival PI3K-AKT cascade, thereby changing a balance between cell death and survival. Suppression of JNK activation partially reduced CBD-induced cell death in 3D GBM cultures. In contrast, co-treatment of CBD-targeted cells with inhibitors of PI3K-AKT-NF-κB, IKK-NF-κB or JAK2-STAT3 pathways killed surviving GBM cells in both 2D and 3D cultures, potentially improving the therapeutic ratio of GBM.

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Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer

Abstract

According to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood. Here, CBD promoted cell death in gastric cancer. We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction. Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.

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ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma

Abstract

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. SIGNIFICANCE: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.

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Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

Abstract

The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.

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