Tag: cancer

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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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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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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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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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