cannabidiol and Glioblastoma

The increased incidence of Glioblastoma Multiforme, the most aggressive and most common primary brain tumour, is evident worldwide. Survival rates are reaching only 15 months due to its high recurrence and resistance to current combination therapies including oncotomy, radiotherapy and chemotherapy. Light has been shed in the recent years on the anticancer properties of cannabinoids from Cannabis sativa.. To determine whether cannabinoids alone or in combination with radiotherapy and/or chemotherapy inhibit tumour progression, induce cancer cell death, inhibit metastasis and invasiveness and the mechanisms that underlie these actions.. PubMed and Web of Science were used for a systemic search to find studies on the anticancer effects of natural cannabinoids on glioma cancer cells in vitro and/or in vivo.. A total of 302 papers were identified, of which 14 studies were found to fit the inclusion criteria. 5 studies were conducted in vitro, 2 in vivo and 7 were both in vivo and in vitro. 3 studies examined the efficacy of CBD, THC and TMZ, 1 study examined CBD and radiation, 2 studies examined efficacy of THC only and 3 studies examined the efficacy of CBD only. 1 study examined the efficacy of CBD, THC and radiotherapy, 2 studies examined the combination of CBD and THC and 2 more studies examined the efficacy of CBD and TMZ.. The evidence in this systematic review leads to the conclusion that cannabinoids possess anticancer potencies against glioma cells, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence in order to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for GBM treatment.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cannabidiol; Cannabinoids; Glioblastoma; Humans; Mice

Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM.. Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored.. The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.. With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.. ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cannabidiol; Dose-Response Relationship, Drug; Double-Blind Method; Dronabinol; Drug Combinations; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Oral Sprays; Precision Medicine; Survival Analysis; Temozolomide; Treatment Outcome

Topics: Animals; Brain Neoplasms; Cannabidiol; Cell Line, Tumor; Ecosystem; Glioblastoma; Humans; Immunity, Innate; Lymphocytes; Mice; Tumor Microenvironment

Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor; however, treatment remains a significant challenge. This study aims to identify drug repurposing or repositioning candidates for GBM by developing an integrative rare disease profile network containing heterogeneous types of biomedical data.. We developed a Glioblastoma-based Biomedical Profile Network (GBPN) by extracting and integrating biomedical information pertinent to GBM-related diseases from the NCATS GARD Knowledge Graph (NGKG). We further clustered the GBPN based on modularity classes which resulted in multiple focused subgraphs, named mc_GBPN. We then identified high-influence nodes by performing network analysis over the mc_GBPN and validated those nodes that could be potential drug repurposing or repositioning candidates for GBM.. We developed the GBPN with 1,466 nodes and 107,423 edges and consequently the mc_GBPN with forty-one modularity classes. A list of the ten most influential nodes were identified from the mc_GBPN. These notably include Riluzole, stem cell therapy, cannabidiol, and VK-0214, with proven evidence for treating GBM.. Our GBM-targeted network analysis allowed us to effectively identify potential candidates for drug repurposing or repositioning. Further validation will be conducted by using other different types of biomedical and clinical data and biological experiments. The findings could lead to less invasive treatments for glioblastoma while significantly reducing research costs by shortening the drug development timeline. Furthermore, this workflow can be extended to other disease areas.

Topics: Cannabidiol; Drug Development; Drug Repositioning; Glioblastoma; Humans; Rare Diseases

Cannabis and its derivatives are being used increasingly by patients with cancer, including patients with glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy. Despite promising preclinical data suggesting potential anti-cancer effects for cannabinoids in GBM, clinical and safety data are lacking. This editorial will discuss a recent Phase 1b trial of nabiximols oromucosal spray in combination with dose-intense temozolomide in patients with recurrent GBM in the context of other relevant findings in this field.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cannabidiol; Cell Proliferation; Cell Survival; Clinical Trials, Phase I as Topic; Dronabinol; Drug Combinations; Glioblastoma; Humans; Oral Sprays; Temozolomide; Treatment Outcome

Cannabidiol (CBD) has been shown to slow cancer cell growth and is toxic to human glioblastoma cell lines. Thus, CBD could be an effective therapeutic for glioblastoma. In the present study, we explored the anticancer effect of cannabidiol loaded magnesium-gallate (CBD/Mg-GA) metal-organic framework (MOF) using the rat glioma brain cancer (C6) cell line. Bioactive and microporous magnesium gallate MOF was employed for simultaneous delivery of two potential anticancer agents (gallic acid and CBD) to the cancer cells. Gallic acid (GA), a polyphenolic compound, is part of the MOF framework, while CBD is loaded within the framework. Slow degradation of CBD/Mg-GA MOF in physiological fluids leads to sustained release of GA and CBD. CBD's anti-cancer actions target mitochondria, inducing their dysfunction and generation of harmful reactive oxygen species (ROS). Anticancer effects of CBD/Mg-GA include a significant increase in ROS production and a reduction in anti-inflammatory responses as reflected by a significant decrease in TNF-α expression levels. Molecular mechanisms that underlie these effects include the modulation of NF-κB expression, triggering the apoptotic cascades of glioma cells. CBD/Mg-GA MOF has potential anti-cancer, anti-inflammatory and anti-oxidant properties. Thus, the present study demonstrates that CBD/Mg-GA MOF may be a promising therapeutic for glioblastoma.

Topics: Antineoplastic Agents; Cannabidiol; Cell Line, Tumor; Cell Proliferation; Drug Carriers; Gallic Acid; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Magnesium; Metal-Organic Frameworks; NF-kappa B; Reactive Oxygen Species

The transcription factor NF-κB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-κB activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive.. In a pharmacogenomics study with a panel of transgenic glioma cells, we observed that NF-κB can be converted into a tumor suppressor by the non-psychotropic cannabinoid cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study, we performed pharmacological assays, gene expression profiling, biochemical, and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM datasets.. We found that CBD promotes DNA binding of the NF-κB subunit RELA and simultaneously prevents RELA phosphorylation on serine-311, a key residue that permits genetic transactivation. Strikingly, sustained DNA binding by RELA-lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen species (ROS), while high ROS content in other tumors blocked CBD-induced hGSC death. Consequently, ROS levels served as a predictive biomarker for CBD-sensitive tumors.. This evidence demonstrates how a clinically approved drug can convert NF-κB into a tumor suppressor and suggests a promising repurposing option for GBM therapy.

Topics: Antioxidants; Apoptosis; Cannabidiol; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; NF-kappa B; Transcription Factor RelA; Tumor Suppressor Proteins

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.

Topics: Apoptosis; Autophagy; Brain Neoplasms; Cannabidiol; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Janus Kinase 2; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Radiation Tolerance; Signal Transduction; STAT3 Transcription Factor

Grade IV glioblastoma multiforme is a deadly disease, with a median survival of around 14 to 16 months. Maximal resection followed by adjuvant radiochemotherapy has been the mainstay of treatment since many years, although survival is only extended by a few months. In recent years, an increasing number of data from in vitro and in vivo research with cannabinoids, particularly with the non-intoxicating cannabidiol (CBD), point to their potential role as tumour-inhibiting agents. Herein, a total of nine consecutive patients with brain tumours are described as case series; all patients received CBD in a daily dose of 400 mg concomitantly to the standard therapeutic procedure of maximal resection followed by radiochemotherapy. By the time of the submission of this article, all but one patient are still alive with a mean survival time of 22.3 months (range=7-47 months). This is longer than what would have been expected.

Topics: Adolescent; Adult; Brain Neoplasms; Cannabidiol; Chemoradiotherapy, Adjuvant; Child, Preschool; Combined Modality Therapy; Female; Glioblastoma; Humans; Male; Middle Aged; Survival Rate

The therapeutic potential of cannabinoids has been truly constrained heretofore due to their strong psychoactive effects and their high lipophilicity. In this context, precisely due to the lack of psychoactive properties, cannabidiol (CBD), the second major component of Cannabis sativa, arises as the phytocannabinoid with the most auspicious therapeutic potential. Hence, the incorporation of CBD in lipid nanocapsules (LNCs) will contribute to overcome the dosing problems associated with cannabinoids. Herein, we have prepared LNCs decorated and loaded with CBD for glioma therapy and screened in vitro their critical parameters. On the one hand, we have encapsulated CBD into the oily core of LNCs to test their in vitro efficacy as extended-release carriers against the human glioblastoma cell line U373MG. The in vitro antitumor effect was highly dependent on the size of LNCs due to its pivotal role in the extent of CBD release. Effectively, a comparison between two differently-sized LNCs (namely, 20-nm and 50-nm sized carriers) showed that the smaller LNCs reduced by 3.0-fold the IC

Topics: Antineoplastic Agents; Cannabidiol; Cannabis; Cell Line, Tumor; Delayed-Action Preparations; Drug Screening Assays, Antitumor; Excipients; Glioblastoma; Humans; Inhibitory Concentration 50; Lipids; Nanocapsules; Particle Size

Topoisomerase II (Topo2) inhibitors in combination with cisplatin represent a common treatment modality used for glioma patients. The main mechanism of their action involves induction of DNA double-strand breaks (DSBs). DSBs are repaired via the homology-dependent DNA repair (HRR) and non-homologous end-joining (NHEJ). Inhibition of the NHEJ or HRR pathway sensitizes cancer cells to the treatment. In this work, we investigated the effect of three Topo2 inhibitors-etoposide, NK314, or HU-331 in combination with cisplatin in the U-87 human glioblastoma cell line. Etoposide as well as NK314 inhibited Topo2 activity by stabilizing Topo2-DNA cleavable complexes whereas HU-331 inhibited the ATPase activity of Topo2 using a noncompetitive mechanism. To increase the effectiveness of the treatment, we combined cisplatin and Topo2 inhibitor treatment with DSB repair inhibitors (DRIs). The cells were sensitized with NHEJ inhibitor, NU7441, or the novel HRR inhibitor, YU238259, prior to drug treatment. All of the investigated Topo2 inhibitors in combination with cisplatin efficiently killed the U-87 cells. The most cytotoxic effect was observed for the cisplatin + HU331 treatment scheme and this effect was significantly increased when a DRI pretreatment was used; however, we did not observed DSBs. Therefore, the molecular mechanism of cytotoxicity caused by the cisplatin + HU331 treatment scheme is yet to be evaluated. We observed a concentration-dependent change in DSB levels and accumulation at the G2/M checkpoint and S-phase in glioma cells incubated with NK314/cisplatin and etoposide/cisplatin. In conclusion, in combination with cisplatin, HU331 is the most potent Topo2 inhibitor of human glioblastoma cells.

Topics: Apoptosis; Benzamides; Brain Neoplasms; Cannabidiol; Cell Cycle; Cell Line, Tumor; Chromones; Cisplatin; DNA Breaks, Double-Stranded; DNA Repair; Etoposide; Glioblastoma; Humans; Morpholines; Phenanthrenes; Sulfonamides; Topoisomerase II Inhibitors

Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease. Previous observations by our group and others have shown that Δ

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cannabidiol; Cell Line, Tumor; Dronabinol; Female; Glioblastoma; Humans; Male; Mice, Nude; Neoplastic Stem Cells; Temozolomide; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cannabidiol; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Damage; Drug Synergism; Glioblastoma; Humans; Mice; Neural Stem Cells; Signal Transduction

Glioblastoma (GBM) resistance to therapy is the most common cause of tumor recurrence, which is ultimately fatal in 90% of the patients 5 years after initial diagnosis. A sub-population of tumor cells with stem-like properties, glioma stem cells (GSCs), is specifically endowed to resist or adapt to the standard therapies, leading to therapeutic resistance. Several anticancer agents, collectively termed redox therapeutics, act by increasing intracellular levels of reactive oxygen species (ROS). In this study, we investigated mechanisms underlying GSC response and resistance to cannabidiol (CBD), a non-toxic, non-psychoactive cannabinoid and redox modulator. Using primary GSCs, we showed that CBD induced a robust increase in ROS, which led to the inhibition of cell survival, phosphorylated (p)-AKT, self-renewal and a significant increase in the survival of GSC-bearing mice. Inhibition of self-renewal was mediated by the activation of the p-p38 pathway and downregulation of key stem cell regulators Sox2, Id1 and p-STAT3. Following CBD treatment, a subset of GSC successfully adapted, leading to tumor regrowth. Microarray, Taqman and functional assays revealed that therapeutic resistance was mediated by enhanced expression of the antioxidant response system Xc catalytic subunit xCT (SLC7A11 (solute carrier family 7 (anionic amino-acid transporter light chain), member 11)) and ROS-dependent upregulation of mesenchymal (MES) markers with concomitant downregulation of proneural (PN) markers, also known as PN-MES transition. This 'reprogramming' of GSCs occurred in culture and in vivo and was partially due to activation of the NFE2L2 (NRF2 (nuclear factor, erythroid 2-like)) transcriptional network. Using genetic knockdown and pharmacological inhibitors of SLC7A11, we demonstrated that combining CBD treatment with the inhibition of system Xc resulted in synergistic ROS increase leading to robust antitumor effects, that is, decreased GSC survival, self-renewal, and invasion. Our investigation provides novel mechanistic insights into the antitumor activity of redox therapeutics and suggests that combinatorial approaches using small molecule modulators of ROS offer therapeutic benefits in GBM.

Topics: Amino Acid Transport System y+; Animals; Antioxidants; Apoptosis; Cannabidiol; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Glioblastoma; Mesoderm; Mice, Nude; Models, Biological; Neoplastic Stem Cells; Neurons; NF-E2-Related Factor 2; Phenotype; Piperazines; Reactive Oxygen Species; RNA, Small Interfering; Survival Analysis; Up-Regulation; Xenograft Model Antitumor Assays

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.

Topics: Brain Neoplasms; Cannabidiol; Cell Line, Tumor; Glioblastoma; Humans; TRPV Cation Channels

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

Topics: Animals; Brain Neoplasms; Cannabidiol; Cell Line, Tumor; Female; Glioblastoma; Humans; Inhibitor of Differentiation Protein 1; Mice; Mice, Nude; Neoplasm Invasiveness; Neurospora; RNA Interference; Transplantation, Heterologous; Up-Regulation

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cannabidiol; Cannabis; Cell Proliferation; Dronabinol; Drug Delivery Systems; Glioblastoma; Humans; Mice; Polymers; Transplantation, Heterologous

The cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor agonist Delta(9)-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB(1) and CB(2) receptors, can modulate the actions of Delta(9)-THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Delta(9)-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Delta(9)-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Delta(9)-THC. In the U251 and SF126 glioblastoma cell lines, Delta(9)-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Delta(9)-THC may improve the overall effectiveness of Delta(9)-THC in the treatment of glioblastoma in cancer patients.

Topics: Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cannabidiol; Caspases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dronabinol; Drug Screening Assays, Antitumor; Drug Synergism; Glioblastoma; Humans; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Neoplasm Proteins; Reactive Oxygen Species; Receptor, Cannabinoid, CB2