Tag: cannabidiol

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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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Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells

This research was done in vitro, results in vitro do not always carry over to human trials.

Results

Results obtained indicate that both cannabidiol and Cannabis sativa extracts were able to halt cell proliferation in all cell lines at varying concentrations. They further revealed that apoptosis was induced by cannabidiol as shown by increased subG0/G1 and apoptosis through annexin V. Apoptosis was confirmed by overexpression of p53, caspase 3 and bax. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels.

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Isolated cannabidiol from Cannabis sativa plant extracts inhibit growth and induce apoptosis in cervical cancer cells

Abstract

Cervical cancer remains a global health related issue among females of Sub-Saharan Africa, with over half a million new cases reported each year. Different therapeutic regimens have been suggested in various regions of Africa, however, over a quarter of a million women die of cervical cancer, annually. Therefore, it is important to search for new drugs through effective screening of medicinal plant extracts to identify lead anti-cervical cancer drugs. The aim of this study was to evaluate for the anti-growth effects of Cannabis sativa extracts and its isolate, cannabidiol on cervical cancer cell lines HeLa, SiHa, and ME-180. To determine for the presence of important constituents and evaluate for the anti-growth effects, phytochemical screening, MTT assay, cell growth analysis, flow cytometry, morphology analysis, Western blot, caspase 3/7 assay, and ATP measurement assay were conducted were conducted. Results obtained indicate that both plant extracts induced cell death at an IC50 of 50 – 100μg/ml and the Inhibition of cell growth was cell line dependent. Flow cytometry confirmed that, with or without cell cycle arrest, the type of induced cell death was apoptosis. Cannabis sativa extracts led to the up-regulation of apoptosis proteins (p53, Bax, caspase-3, and caspase-9) and the down regulation of anti-apoptosis proteins (Bcl-2 and RBBP6), signalling the execution of apoptosis. Apoptosis induction was further confirmed by morphological changes, an increase in Caspase 3/7 and a decrease in the ATP levels. In conclusion, this data implies Cannabis sativa crude extracts has the potential to inhibit growth and induce apoptosis in cervical cancer cell lines, which may be due to the presence of cannabidiol.

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Id-1 is a Key Transcriptional Regulator of Glioblastoma Aggressiveness and a Novel Therapeutic Target

Abstract

Glioblastoma (GBM) is the most common form of primary adult brain tumors. A majority of GBMs grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable. It is, therefore, essential to discover master regulators that control GBM invasiveness and target them therapeutically. We demonstrate here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of GBM cell lines and primary GBM cells. Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathological grades in patient biopsies. Id-1 knockdown dramatically reduces GBM cell invasion that is accompanied by profound morphological changes and robust reduction in expression levels of “mesenchymal” markers, as well as inhibition of self-renewal potential and down-regulation of glioma stem cell markers. Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human GBM. Furthermore, we show that a non-toxic compound, cannabidiol, significantly down-regulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal. Additionally, cannabidiol significantly inhibits the invasion of GBM cells through an organotypic brain slice and glioma progression in vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways in GBM, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of GBM patients.

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Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents

Abstract

The aggressive behavior of Glioblastoma multiforme (GBM) is mainly due to high invasiveness and proliferation rate as well as to high resistance to standard chemotherapy. Several chemotherapeutic agents like temozolomide (TMZ), carmustine (BCNU) or doxorubicin (DOXO) have been employed for treatment of GBM, but they display limited efficacy. Therefore, it is important to identify new treatment modalities to improve therapeutic effects and enhance GBM chemosensitivity. Recently, activation of the transient receptor potential vanilloid type 2 (TRPV2) has been found to inhibit human GBM cell proliferation and overcome BCNU resistance of GBM cells. Herein, we evaluated the involvement of cannabidiol (CBD)-induced TRPV2 activation, in the modulation of glioma cell chemosensitivity to TMZ, BCNU and DOXO. We found that CBD increases TRPV2 expression and activity. CBD by triggering TRPV2-dependent Ca 2+ influx increases drug uptake and synergizes with cytotoxic agents to induce apoptosis of glioma cells, whereas no effects were observed in normal human astrocytes. Moreover, as the pore region of transient receptor potential (TRP) channels is critical for ion channel permeation, we demonstrated that deletion of TRPV2 poredomain inhibits CBD-induced Ca 2+influx, drug uptake and cytotoxic effects. Overall, we demonstrated that co-administration of cytotoxic agents together with the TRPV2 agonist CBD increases drug uptake and parallelly potentiates cytotoxic activity in human glioma cells.

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Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer

Abstract

Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB1-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.

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Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

Although cannabinoids exhibit a broad variety of anticarcinogenic effects, their potential use in cancer therapy is limited by their psychoactive effects. Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion. Using Matrigel invasion assays we found a cannabidiol-driven impaired invasion of human cervical cancer (HeLa, C33A) and human lung cancer cells (A549) that was reversed by antagonists to both CB1 and CB2receptors as well as to transient receptor potential vanilloid 1 (TRPV1). The decrease of invasion by cannabidiol appeared concomitantly with upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). Knockdown of cannabidiol-induced TIMP-1 expression by siRNA led to a reversal of the cannabidiol-elicited decrease in tumor cell invasiveness, implying a causal link between the TIMP-1-upregulating and anti-invasive action of cannabidiol. P38 and p42/44 mitogen-activated protein kinases were identified as upstream targets conferring TIMP-1 induction and subsequent decreased invasiveness. Additionally, in vivo studies in thymic-aplastic nude mice revealed a significant inhibition of A549 lung metastasis in cannabidiol-treated animals as compared to vehicle-treated controls. Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.

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