cannabidiol and Brain-Neoplasms

The potential medicinal properties of Cannabis continue to garner attention, especially in the brain tumor domain. This attention is centered on quality of life and symptom management; however, it is amplified by a significant lack of therapeutic choices for this specific patient population. While the literature on this matter is young, published and anecdotal evidence imply that cannabis could be useful in treating chemotherapy-induced nausea and vomiting, stimulating appetite, reducing pain, and managing seizures. It may also decrease inflammation and cancer cell proliferation and survival, resulting in a benefit in overall patient survival. Current literature poses the challenge that it does not provide standardized guidance on dosing for the above potential indications and cannabis use is dominated by recreational purposes. Furthermore, integrated and longitudinal studies are needed but these are a challenge due to arcane laws surrounding the legality of such substances. The increasing need for evidence-based arguments about potential harms and benefits of cannabis, not only in cancer patients but for other medical use and recreational purposes, is desperately needed.

Topics: Brain Neoplasms; Cannabidiol; Cannabinoids; Cannabis; Humans; Quality of Life

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

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

Glioma-related epilepsy significantly impact on patients' quality of life, and can often be difficult to treat. Seizures cause significant morbidity for example neurocognitive deterioration, which may result from seizures themselves or due to adverse effects from antiepileptic drugs. Management of tumour with surgery, radiotherapy and chemotherapy may contribute to seizure control, but tumour related epilepsy is often refractory despite adequate treatment with standard anti-epileptic medications. Given the increasing interest in medicinal cannabis (or cannabidiol or CBD) as an anti-epileptic drug, CBD may help with seizure control in glioma patients with treatment-refractory seizures. Here we present a case of a young lady with recurrent glioma who had refractory seizures despite multiple anti-epileptic agents, who had significant benefit with CBD.

Topics: Adult; Anticonvulsants; Brain Neoplasms; Cannabidiol; Drug Resistant Epilepsy; Female; Glioma; Humans; Seizures

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

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 form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease. Δ

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cannabidiol; Carmustine; Cell Line, Tumor; Dronabinol; Glioma; Heterografts; Humans; Male; Mice, Nude; Temozolomide

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

Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.

Topics: Alternative Splicing; Autophagy; Brain Neoplasms; Cannabidiol; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Core Binding Factor Alpha 2 Subunit; Glioma; Humans; Neoplastic Stem Cells; Signal Transduction; TRPV Cation Channels; Up-Regulation

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