Tag: cannabidiol

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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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Dramatic response to Laetrile and cannabidiol (CBD) oil in a patient with metastatic low grade serous ovarian carcinoma

Highlights

  • Complimentary alternative medicine use is common in women with gynecologic cancers.
  • Cannabinoid receptors are potential therapeutic targets in ovarian cancer.
  • Communication with patients is critical regarding use of alternative therapies.

Keywords: Cannabidol, Laetrile, Low grade ovarian cancer, Complimentary alternative medicine

Introduction

Low grade serous ovarian cancer (LGSOC) is a rare subtype of serous epithelial ovarian cancer, comprising approximately 10% of all cases of serous carcinoma. The majority of women are diagnosed with advanced stage disease, despite its slow growth. Treatment options for advanced disease include neoadjuvant chemotherapy followed by interval surgical cytoreduction or primary surgical resection followed by adjuvant therapy as well as maintenance hormonal therapy (National Comprehensive Cancer Network, 2019). Adjuvant therapy traditionally consists of combination platinum and taxane based chemotherapy, although response rates are limited, and may include concurrent/maintenance hormonal therapy. Even with advanced stage at diagnosis, patients with LGSOC have an improved prognosis when compared to their high grade serous counterparts, with median overall survival of approximately 100 months reported, reflective of a protracted clinical course (Gershenson et al., 2015).

In an effort to improve oncologic outcomes, investigators have attempted to capitalize on molecular aberrations identified in LGSOC specimens. Most recently, the utilization of MEK inhibitors have been explored due to noted activation of the mitogen-activate protein kinase (MAPK) pathway in LGSOC. A phase II trial evaluating Selumatib activity in women with recurrent LGSOC (GOG 0239) demonstrated a 15% overall response rate, catalyzing the development of phase III trials examining alternate agents in this setting (Farley et al., 2013). A phase III study evaluating Trametinib vs. physicians choice chemotherapy in patients with recurrent or progressive LGSOC (GOG-281) has closed to accrual and will help guide further management with these targeted agents. Furthermore, efforts to identify appropriate patient subsets based on molecular profiling are ongoing. In context of the above, optimal management of these relatively chemotherapy-resistant tumors due to their low-grade nature remains an active area of investigation.

In addition to standard treatments, an increasing proportion of patients are exploring and incorporating complimentary alternative medicine (CAM) for the management of their cancers. Use of CAM is common among gynecologic cancer patients, although many patients may not disclose use to their treating physician. Women who are older are more likely to use CAM either in conjunction with standard treatment or alone, as compared to their younger or male counterparts (Gansler et al., 2008). These therapies may or may not be recommended by their primary oncologist, and many have not been evaluated in a clinical trial setting.

In this case report, we present a woman with LGSOC who declined primary systemic chemotherapy followed by interval surgical resection and opted for CAM therapy with Laetrile (amygdalin) and cannabidol (CBD) oil. The patient has granted permission for this publication.

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Where to buy laetrile? Richardson Nutritional Center
Where to buy CBD? Epiphany Canna Solutions

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Cannabidiol Affects Extracellular Vesicle Release, miR21 and miR126, and Reduces Prohibitin Protein in Glioblastoma Multiforme Cells

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumor in adults, with poor prognosis. Extracellular vesicles (EVs) are key-mediators for cellular communication through transfer of proteins and genetic material. Cancers, such as GBM, use EV release for drug-efflux, pro-oncogenic signaling, invasion and immunosuppression; thus the modulation of EV release and cargo is of considerable clinical relevance. As EV-inhibitors have been shown to increase sensitivity of cancer cells to chemotherapy, and we recently showed that cannabidiol (CBD) is such an EV-modulator, we investigated whether CBD affects EV profile in GBM cells in the presence and absence of temozolomide (TMZ). Compared to controls, CBD-treated cells released EVs containing lower levels of pro-oncogenic miR21 and increased levels of anti-oncogenic miR126; these effects were greater than with TMZ alone. In addition, prohibitin (PHB), a multifunctional protein with mitochondrial protective properties and chemoresistant functions, was reduced in GBM cells following 1 h CBD treatment. This data suggests that CBD may, via modulation of EVs and PHB, act as an adjunct to enhance treatment efficacy in GBM, supporting evidence for efficacy of cannabinoids in GBM.

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Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells

Abstract

Despite advances in glioblastoma (GBM) therapy, prognosis of the disease remains poor with a low survival rate. Cannabidiol (CBD) can induce cell death and enhance radiosensitivity of GBM but not normal astrocytes. Inhibition of ATM kinase is an alternative mechanism for radiosensitization of cancer cells. In this study, we increased the cytotoxic effects of the combination of CBD and γ-irradiation in GBM cells through additional inhibition of ATM kinase with KU60019, a small molecule inhibitor of ATM kinase. We observed in GBM cells treated by CBD, γ-irradiation and KU60019 high levels of apoptosis together with strong upregulation of the percentage of G2/M-arrested cells, blockade of cell proliferation and a massive production of pro-inflammatory cytokines. Overall, these changes caused both apoptotic and non-apoptotic inflammation-linked cell death. Furthermore, via JNK-AP1 activation in concert with active NF-κB, CBD upregulated gene and protein expression of DR5/TRAIL-R2 and sensitize GBM cells to TRAIL-induced apoptosis. In contrast, CBD notably decreased in GBM surface levels of PD-L1, a critical immune checkpoint agent for T-lymphocytes. We also used in the present study TS543 human proneural glioma cells that were grown as spheroid culture. TS543 neurospheres exhibited dramatic sensitivity to CBD-mediated killing that was additionally increased in combination with γ-irradiation and KU60019. In conclusion, treatment of human GBM by the triple combination (CBD, γ-irradiation and KU60019) could significantly increase cell death levels in vitro and potentially improve the therapeutic ratio of GBM.

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