Category: 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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Can cannabidiol inhibit angiogenesis in colon cancer?

Abstract

Colon cancer is the third most common human malignancy and a main cause of death worldwide. The current study was carried out to investigate the effects of cannabidiol, a cannabinoid, on angiogenesis and cell death in mice with experimental colon cancer induced by injection of CT26 cell line. Fifty male BALB/c mice were assigned randomly to five study groups, including: (1) negative control, (2) cancer control, (3) cancer vehicle control, (3) cancer treatment (1 mg/kg cannabidiol), and (5) cancer treatment (5 mg/kg cannabidiol). Treatment responses were evaluated based on histopathological examination, the expression of vascular endothelial growth factor (VEGF) gene, measurement of interleukins (ILs 6 and 8), oxidative stress parameters (glutathione peroxidase, glutathione reductase, superoxide dismutase serum activities, total antioxidant capacity, and malondialdehyde levels). In the present study, CBD reduced VEGF gene expression, decreased serum levels of IL6, IL8, and malondialdehyde, and increased antioxidant enzyme activity in mice with colon cancer. Moreover, cannabidiol induced apoptosis and reduced cellular pleomorphism. Cannabidiol can be potentially considered as an anti-colon cancer medicine as it exerts an inhibitory effect on angiogenesis, tumor growth, and metastasis through reducing VEGF gene expression, decreasing cytokines, and increasing antioxidant enzyme activities.

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Regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The challenging problem in cancer treatment is to find a way to upregulate radiosensitivity of GBM while protecting neurons and neural stem/progenitor cells in the brain. The goal of the present study was upregulation of the cytotoxic effect of γ-irradiation in GBM by non-psychotropic and non-toxic cannabinoid, cannabidiol (CBD). We emphasized three main aspects of signaling mechanisms induced by CBD treatment (alone or in combination with γ-irradiation) in human GBM that govern cell death: 1) CBD significantly upregulated the active (phosphorylated) JNK1/2 and MAPK p38 levels with the subsequent downregulation of the active phospho-ERK1/2 and phospho-AKT1 levels. MAPK p38 was one of the main drivers of CBD-induced cell death, while death levels after combined treatment of CBD and radiation were dependent on both MAPK p38 and JNK. Both MAPK p38 and JNK regulate the endogenous TRAIL expression. 2) NF-κB p65-P(Ser536) was not the main target of CBD treatment and this transcription factor was found at high levels in CBD-treated GBM cells. Additional suppression of p65-P(Ser536) levels using specific small molecule inhibitors significantly increased CBD-induced apoptosis. 3) CBD treatment substantially upregulated TNF/TNFR1 and TRAIL/TRAIL-R2 signaling by modulation of both ligand and receptor levels followed by apoptosis. Our results demonstrate that radiation-induced death in GBM could be enhanced by CBD-mediated signaling in concert with its marginal effects for neural stem/progenitor cells and astrocytes. It will allow selecting efficient targets for sensitization of GBM and overcoming cancer therapy-induced severe adverse sequelae.

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Inhibition of cervical cancer cell proliferation by cannabidiol

Seventy phytocannabinoids are now known to be synthesized by Cannabis sativa (marijuana) [1]. The major non-psychoactive cannabinoid cannabidiol (CBD) exhibits antiproliferative effects against breast, cervix, colon, glioma, leukemia, ovary, prostate, and thyroid cancer cells [2]. In this study, we investigated the antiproliferative effect of CBD on the ME-180 cervical cancer cell line. The cells were plated at subconfluent density in DMEM-F12 medium containing 10% fetal bovine serum (FBS), and the experiments were carried out in the serum-free medium. CBD inhibited the proliferation of these cells with an IC50 value of approximately 6µM. At 10µM, CBD induced apoptosis of nearly all cells within 24 hours (figure below). However, within few hours of treatment with CBD, the cells also exhibited numerous cytoplasmic vacuoles, reminiscent of paraptosis. Significant reversal of the CBD-induced inhibition of proliferation was observed in the presence of antioxidant α-tocopherol (200µM), Trolox (200µM), peroxisome proliferator-activated receptor-γ antagonist GW9662 (2µM), and ceramidase inhibitor L-cycloserine (100µM). Limited reversal of inhibition of proliferation was also observed in the presence of 2µM of cannabinoid receptor (CB) antagonist AM251 (CB1). Nevertheless, the cytoplasmic vacuoles observed in the presence of CBD persisted in the presence of these compounds, with the exception of α-tocopherol and Trolox. The results of our study suggest that CBD exerts its antiproliferative effect via multiple mechanisms, and it could be a potential treatment for cervical cancer.

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Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

Abstract

Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs.

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