The Combination of Δ 9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins


“Phytocannabinoids represent a promising approach in glioblastoma therapy.

Previous work has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations of psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly increases cell death.

In the present work, the glioblastoma cell lines U251MG and U138MG were used to investigate whether the combination of THC and CBD in a 1:1 ratio is associated with a disruption of cellular energy metabolism, and whether this is caused by affecting mitochondrial respiration.

Here, the combined administration of THC and CBD (2.5 µM each) led to an inhibition of oxygen consumption rate and energy metabolism. These effects were accompanied by morphological changes to the mitochondria, a release of mitochondrial cytochrome c into the cytosol and a marked reduction in subunits of electron transport chain complexes I (NDUFA9, NDUFB8) and IV (COX2, COX4). Experiments with receptor antagonists and inhibitors showed that the degradation of NDUFA9 occurred independently of the activation of the cannabinoid receptors CB1, CB2 and TRPV1 and of usual degradation processes mediated via autophagy or the proteasomal system.

In summary, the results describe a previously unknown mitochondria-targeting mechanism behind the toxic effect of THC and CBD on glioblastoma cells that should be considered in future cancer therapy, especially in combination strategies with other chemotherapeutics.”

“Cannabidiol (CBD) is a phytocannabinoid from Cannabis sativa L. that exhibits no psychoactivity and, like the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC), shows anticancer effects in preclinical cell and animal models. Previous studies have indicated a stronger cancer-targeting effect when THC and CBD are combined. Here, we investigated how the combination of THC and CBD in a 1:1 ratio affects glioblastoma cell survival. The compounds were found to synergistically enhance cell death, which was attributed to mitochondrial damage and disruption of energy metabolism. A detailed look at the mitochondrial electron transfer chain showed that THC/CBD selectively decreased certain subunits of complexes I and IV. These data highlight the fundamental changes in cellular energy metabolism when cancer cells are exposed to a mixture of cannabinoids and underscore the potential of combining cannabinoids in cancer treatment.”

The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients

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“The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment.

Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients’ disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups.

Most outcome measures improved significantly during MC treatment for most patients (p < 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82–157) at baseline to 89 (45–138) at endpoint (−18.98; 95%CI= −26.95 to −11.00; p < 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment.

The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.

The main finding of the current study is that most cancer comorbid symptoms improved significantly during 6 months of MC treatment.

Additionally, we found that MC treatment in cancer patients was well tolerated and safe.”

“Cancer Pain Treatment Using Marijuana Safe and Effective, Large Study Finds”

Cannabinol inhibits proliferation and induces cell cycle arrest and apoptosis in glioblastoma, hepatocellular carcinoma and breast cancer cells

“Cannabis sativa is an agriculturally and medicinally important plant with many pharmaceutical properties. Cancer is a deadly disease; it is estimated that it will cause over 80 thousand deaths in 2019 in Canada.

Although numerous studies have demonstrated that cannabinoids have anti-tumorous properties in various cancers, the anti-malignant activities of cannabinol (CBN) on carcinogenesis and underlying mechanisms remain largely unknown.

In this study, we provide evidence that CBN inhibits proliferation of A172, HB8065 and HCC1806 cells in a dose- and time-dependent manner. CBN regulates expression of cannabinoid receptors, CB2, GPR55 and GPR18 in different cell lines, while reducing levels of phosphorylated ERK1/2 in HCC1806 and phosphorylated AKT in A172 and HB8065 cells.

We find that CBN induces apoptosis through downregulation of p21 and p27 and a G1 or S-phase cell cycle arrest through a dose-dependent downregulation of cyclin E1, CDK1 and CDK2.

These data support the medicinal potential of CBN in anti-cancer therapy.”

Biophysical Studies and In Vitro Effects of Tumor Cell Lines of Cannabidiol and Its Cyclodextrin Inclusion Complexes

“Phytocannabinoids possess anticancer properties, as established in vitro and in vivo. However, they are characterized by high lipophilicity. To improve the properties of cannabidiol (CBD), such as solubility, stability, and bioavailability, CBD inclusion complexes with cyclodextrins (CDs) might be employed, offering targeted, faster, and prolonged CBD release. The aim of the present study is to investigate the in vitro effects of CBD and its inclusion complexes in randomly methylated β-CD (RM-β-CD) and 2-hyroxypropyl-β-CD (HP-β-CD). The enhanced solubility of CBD upon complexation with CDs was examined by phase solubility study, and the structure of the inclusion complexes of CBD in 2,6-di-O-methyl-β-CD (DM-β-CD) and 2,3,6-tri-O-methyl-β-CD (TM-β-CD) was determined by X-ray crystallography. The structural investigation was complemented by molecular dynamics simulations. The cytotoxicity of CBD and its complexes with RM-β-CD and HP-β-CD was tested on two cell lines, the A172 glioblastoma and TE671 rhabdomyosarcoma cell lines. Methylated β-CDs exhibited the best inclusion ability for CBD. A dose-dependent effect of CBD on both cancer cell lines and improved efficacy of the CBD-CDs complexes were verified. Thus, cannabinoids may be considered in future clinical trials beyond their palliative use as possible inhibitors of cancer growth.”

Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities

“Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. “

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

“Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons.

Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects.

In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread.

This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.”

“Cannabinoids have been shown to suppress tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition and to induce tumour cell apoptosis, autophagy and immune response. This review focuses on the current status of investigations on the impact of inhibitors of endocannabinoid-degrading enzymes on tumour growth and spread in preclinical oncology research.”

Cannabidiol Μay Prolong Survival in Patients With Glioblastoma Multiforme

“Background: Glioblastoma multiforme (GBM) is a relatively rare type of brain tumour with an incidence rate around 6 per 100,000. Even with the widely practiced combination of radiotherapy with adjuvant temozolomide, the median overall survival remains low with just 13.5 to 16 months after diagnosis.

Patients and methods: We retrospectively reviewed the survival of a cohort of 15 consecutive, unselected patients with histopathologically confirmed glioblastoma multiforme (GBM) who received CBD (400 to 600 mg orally per day) in addition to standard therapy (maximum resection of the tumour followed by radio-chemotherapy).

Results: Of 15 patients, seven (46.7%) are now living for at least 24 months, and four (26.7%) for at least 36 months. This is more than twice as long as has been previously reported in the literature. The mean overall survival is currently 24.2 months (median 21 months).

Conclusion: CBD is a well supported co-medication and seems to prolong the survival of patients with glioblastoma multiforme.”

“In conclusion, concomitant CBD seems to prolong the survival of patients with glioblastoma multiforme; CBD was well supported and did not cause side effects.”

Cannabidiol inhibits RAD51 and sensitizes glioblastoma to temozolomide in multiple orthotopic tumor models

“Background: Cannabidiol (CBD), a nonpsychoactive cannabinoid with a low toxicity profile, has been shown to produce antitumor activity across cancers in part through selective production of reactive oxygen species (ROS) in tumor cells. The alkylating agent, temozolomide (TMZ), is standard of care for treatment of glioblastoma (GBM). It can trigger increased ROS to induce DNA damage. It has also been reported that downregulating the expression of RAD51, an important DNA damage repair protein, leads to sensitization of GBM to TMZ.

Methods: We determined the extent to which CBD enhanced the antitumor activity of TMZ in multiple orthotopic models of GBM. In addition, we investigated the potential for CBD to enhance the antitumor activity of TMZ through production of ROS and modulation of DNA repair pathways.

Results: CBD enhanced the activity of TMZ in U87 MG and U251 GBM cell lines and in patient-derived primary GBM163 cells leading to stimulation of ROS, activation of the ROS sensor AMP-activated protein kinase (AMPK), and upregulation of the autophagy marker LC3A. CBD produced a sensitization of U87 and GBM163-derived intracranial (i.c.) tumors to TMZ and significantly increased survival of tumor-bearing mice. However, these effects were not observed in orthotopic models derived from GBM with intact methylguanine methyltransferase (MGMT) expression. We further demonstrate that CBD inhibited RAD51 expression in MGMT-methylated models of GBM, providing a potential mechanism for tumor sensitization to TMZ by CBD.

Conclusion: These data support the potential therapeutic benefits of using CBD to enhance the antitumor activity of TMZ in GBM patients.”

Plant-derived cannabinoids as anticancer agents

“Substantial preclinical evidence demonstrates the antiproliferative, cytotoxic, and antimetastatic properties of plant-derived cannabinoids (phytocannabinoids) such as cannabidiol and tetrahydrocannabinol. The cumulative body of research into the intracellular mechanisms and phenotypic effects of these compounds supports a logical, judicious progression to large-scale phase II/III clinical trials in certain cancer types to truly assess the efficacy of phytocannabinoids as anticancer agents.”

Cannabinoids as anticancer drugs: current status of preclinical research

“Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ9-tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies.”