Therapeutic targeting of the tumor microenvironments with cannabinoids and their analogs: Update on clinical trials

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“Cancer is a major global public health concern that affects both industrialized and developing nations. Current cancer chemotherapeutic options are limited by side effects, but plant-derived alternatives and their derivatives offer the possibilities of enhanced treatment response and reduced side effects.

A plethora of recently published articles have focused on treatments based on cannabinoids and cannabinoid analogs and reported that they positively affect healthy cell growth and reverse cancer-related abnormalities by targeting aberrant tumor microenvironments (TMEs), lowering tumorigenesis, preventing metastasis, and/or boosting the effectiveness of chemotherapy and radiotherapy.

Furthermore, TME modulating systems are receiving much interest in the cancer immunotherapy field because it has been shown that TMEs have significant impacts on tumor progression, angiogenesis, invasion, migration, epithelial to mesenchymal transition, metastasis and development of drug resistance.

Here, we have reviewed the effective role of cannabinoids, their analogs and cannabinoid nano formulations on the cellular components of TME (endothelial cells, pericytes, fibroblast and immune cells) and how efficiently it retards the progression of carcinogenesis is discussed. The article summarizes the existing research on the molecular mechanisms of cannabinoids regulation of the TME and finally highlights the human studies on cannabinoids’ active interventional clinical trials.

The conclusion outlines the need for future research involving clinical trials of cannabinoids to demonstrate their efficacy and activity as a treatment/prevention for various types of human malignancies.”

Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation

Journal of Integrative Medicine

“Globally, it is evident that glioblastoma multiforme (GBM) is an aggressive malignant cancer with a high mortality rate and no effective treatment options. Glioblastoma is classified as the stage-four progression of a glioma tumor, and its diagnosis results in a shortened life expectancy. Treatment options for GBM include chemotherapy, immunotherapy, surgical intervention, and conventional pharmacotherapy; however, at best, they extend the patient’s life by a maximum of 5 years. GBMs are considered incurable due to their high recurrence rate, despite various aggressive therapeutic approaches which can have many serious adverse effects.

Ceramides, classified as endocannabinoids, offer a promising novel therapeutic approach for GBM. Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells. Cannabinoids promote atypical protein kinase C, deactivate fatty acid amide hydrolase enzymes, and activate transient receptor potential vanilloid 1 (TRPV1) and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids. In previous in vivo studies, endocannabinoids, chemically classified as amide formations of oleic and palmitic acids, have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis.

This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis, which have potential as a novel therapy for GBM.”

“As discussed above, endocannabinoids could prove to be a viable alternative treatment for GBM.”

Therapeutic and Supportive Effects of Cannabinoids in Patients with Brain Tumors (CBD Oil and Cannabis)


“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.”

In Silico Binding Analysis of Cannabinoids with Eph Receptors for Therapeutic Use in Gliomas

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“Background: Accumulating evidence suggests overexpression of Eph receptors is associated with malignant human gliomas. Inhibiting interactions of Eph receptors with their ephrin ligands may improve clinical outcomes in glioma patients. The present study investigated the potential of cannabinoids to bind Eph receptors and block Eph/ephrin interactions.

Methods: Twelve major cannabinoids were computationally docked with ligand binding domains from six glioma-associated Eph receptors through Auto Dock Vina to measure their potential binding affinities. The molecular structures and residue interactions of the most favorable poses for each receptor binding domain were further visually examined.

Results: Cannabichromene (CBC) exhibited the most favorable binding with EphA2, EphA3, and EphB4 receptor ligand binding domains while tetrahydrocannabinol (THC) was predicted to bind favorably with EphB2 and EphB3 receptor ligand binding domains. EphA4 showed the best potential binding affinity with cannabidivarin (CBDV). Further analysis revealed that these cannabinoids bind to specific locations on Eph receptors required for Eph/ephrin interactions.

Conclusion: The findings suggest that certain cannabinoids can effectively bind to hydrophobic pockets required for ephrin binding and thereby be used to block subsequent Eph/ephrin interactions.”

Role of Cannabidiol for Improvement of the Quality of Life in Cancer Patients: Potential and Challenges


“There is currently a growing interest in the use of cannabidiol (CBD) to alleviate the symptoms caused by cancer, including pain, sleep disruption, and anxiety. CBD is often self-administered as an over-the-counter supplement, and patients have reported benefits from its use. However, despite the progress made, the mechanisms underlying CBD’s anti-cancer activity remain divergent and unclear. Herein, we provide a comprehensive review of molecular mechanisms to determine convergent anti-cancer actions of CBD from pre-clinical and clinical studies. In vitro studies have begun to elucidate the molecular targets of CBD and provide evidence of CBD’s anti-tumor properties in cell and mouse models of cancer. Furthermore, several clinical trials have been completed testing CBD’s efficacy in treating cancer-related pain. However, most use a mixture of CBD and the psychoactive, tetrahydrocannabinol (THC), and/or use variable dosing that is not consistent between individual patients. Despite these limitations, significant reductions in pain and opioid use have been reported in cancer patients using CBD or CBD+THC. Additionally, significant improvements in quality-of-life measures and patients’ overall satisfaction with their treatment have been reported. Thus, there is growing evidence suggesting that CBD might be useful to improve the overall quality of life of cancer patients by both alleviating cancer symptoms and by synergizing with cancer therapies to improve their efficacy. However, many questions remain unanswered regarding the use of CBD in cancer treatment, including the optimal dose, effective combinations with other drugs, and which biomarkers/clinical presentation of symptoms may guide its use.”

“CBD has great potential to improve the lives of cancer patients both by alleviating the symptoms of pain, sleep disturbance, and anxiety, but also by synergistic activity with anti-cancer treatments to reverse or eliminate the growth of tumors causing these symptoms. Pre-clinical evidence in cell and mouse models supports the use of CBD as an anti-cancer therapy; however, clinical knowledge is currently lacking in this area. The effectiveness of CBD has been demonstrated in models of lung, breast, and colon cancer, as well as leukemia and glioblastoma. CBD has been shown to be toxic to cancer cells in vitro, and it is also generally well tolerated in the clinic.”

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

Frontiers in Pain Research (@FrontPain) / Twitter

“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. “