Category Archives: Cancer

The Interplay between the Immune and the Endocannabinoid Systems in Cancer

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cells-logo“The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, migration, epithelial-to-mesenchymal transition and stemness. Moreover, agonists of CB1 and CB2 receptors inhibit angiogenesis and lymphangiogenesis in vitro and in vivo. Low-grade inflammation is a hallmark of cancer in the tumor microenvironment (TME), which contains a plethora of innate and adaptive immune cells. These cells play a central role in tumor initiation and growth and the formation of metastasis. CB2 and, to a lesser extent, CB1 receptors are expressed on a variety of immune cells present in TME (e.g., T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, eosinophils). The activation of CB receptors modulates a variety of biological effects on cells of the adaptive and innate immune system. The expression of CB2 and CB1 on different subsets of immune cells in TME and hence in tumor development is incompletely characterized. The recent characterization of the human cannabinoid receptor CB2-Gi signaling complex will likely aid to design potent and specific CB2/CB1 ligands with therapeutic potential in cancer.”

https://pubmed.ncbi.nlm.nih.gov/34064197/

https://www.mdpi.com/2073-4409/10/6/1282

Effects of tetrahydrocannabinols on human oral cancer cell proliferation, apoptosis, autophagy, oxidative stress, and DNA damage

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Archives of Oral Biology“Cannabinoids, including delta-8- and delta-9-tetrahydrocannabinol (THC) have a palliative care impact and may therefore be beneficial against cancer.

The aim of this study was to investigate the effect of Δ9-THC and Δ8-THC on oral cancer cell behaviors.

Results: Both cannabinoids were found to decrease cell viability/proliferation by blocking the cell cycle progression from the S to the G2/M phase and enhancing their apoptosis and autophagy. Δ9-THC and Δ8-THC also suppressed the migration/invasion by inhibiting epithelial-mesenchymal transition markers, such as E-cadherin, in addition to decreasing reactive oxygen species (ROS) production and increasing glutathione (GSH) and the expression of mtMP. Δ9-THC and Δ8-THC also downregulated cyclin D1, p53, NOXA, PUMAα, and DRAM expressions but increased p21 and H2AX expression.

Conclusion: We demonstrated that cannabinoids (Δ9-THC and Δ8-THC) were able to decrease oral cancer cell growth through various mechanisms, including apoptosis, autophagy, and oxidative stress. These results suggest a potential use of these molecules as a therapy against oral cancer.”

https://pubmed.ncbi.nlm.nih.gov/34146926/

“Cannabinoids (Δ9-THC and Δ8-THC) decrease oral cancer cell viability/ proliferation.”

https://www.sciencedirect.com/science/article/abs/pii/S0003996921001631?via%3Dihub

A Phase 2 Randomised Clinical Trial Assessing the Tolerability of Two Different Ratios of Medicinal Cannabis in Patients With High Grade Gliomas

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Frontiers in Oncology (@FrontOncology) | Twitter“Background: Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety.

Methods: A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes.

Results: Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness.

Conclusion: This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing, and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/34094937/

“From this study we have shown that a single nightly dose of THC-containing cannabis was well tolerated in patients in both groups with high-grade gliomas and significantly improved sleep, functional wellbeing and contentment with QoL in a sample of patients compared to baseline. From this trial, the 1:1 ratio has been identified as the preferred combination the moving forward to further trials. This study significantly informs MC product choice for ongoing studies into cannabis being a potential adjunct treatment option for this patient population.”

https://www.frontiersin.org/articles/10.3389/fonc.2021.649555/full

Cannabidiol Modulates Mitochondrial Redox and Dynamics in MCF7 Cancer Cells: A Study Using Fluorescence Lifetime Imaging Microscopy of NAD(P)H

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Archive of "Frontiers in Molecular Biosciences".“The cannabinoid, cannabidiol (CBD), is part of the plant’s natural defense system that when given to animals has many useful medicinal properties, including activity against cancer cells, modulation of the immune system, and efficacy in epilepsy.

Our results support the use of NAD(P)H autofluorescence as an investigative tool and provide further evidence that CBD can modulate mitochondrial function and morphology in a dose-dependent manner, with clear evidence of it inducing oxidative stress at higher concentrations.

This continues to support emerging data in the literature and may provide further insight into its overall mode of action, not only in cancer, but potentially its function in the plant and why it can act as a medicine.”

https://pubmed.ncbi.nlm.nih.gov/34046425/

“Uncontrolled cell growth, or cancer, is frequently associated with increased aerobic glycolysis (the Warburg effect) and alterations in mitochondrial function.

A plant’s ability to develop tumors could explain why so many secondary plant phenolic compounds appear to have anticancer activity in both plant and animal models; over 3,000 species of plants have anticancer activity in animals, with many modulating mitochondrial function and apoptosis

CBD, along with Δ9-tetrahydrocannabinol (THC), is a major phytocannabinoid and both are well described components of medicines.

A growing number of studies have demonstrated the anticancer properties of CBD, in both in vitro and in vivo models.”

https://www.frontiersin.org/articles/10.3389/fmolb.2021.630107/full

Scoping Review and Meta-Analysis Suggests that Cannabis Use May Reduce Cancer Risk in the United States

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View details for Cannabis and Cannabinoid Research cover image“Cannabis use reduces the risk of obesity and cannabinoids inhibit chronic inflammation, known causes of cancer.”

https://pubmed.ncbi.nlm.nih.gov/33998861/

“In addition, in laboratory studies, cannabinoids and other compounds in Cannabis directly inhibit cancer initiation, growth, and spread at the cellular level.”

https://www.liebertpub.com/doi/10.1089/can.2019.0095

Anticancer property of Hemp Bioactive Peptides in Hep3B liver cancer cells through Akt/GSK3β/β-catenin signaling pathway

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Food Science & Nutrition“Foodborne protein hydrolysates exhibit biological activity that may be therapeutic in a number of human disease settings. Hemp peptides (HP) generated by controlled hydrolysis of hemp proteins have a number of health benefits and are of pharmaceutical value. In the present study, we produce small molecular weight HP from hemp seed and investigate its anticancer properties in Hep3B human liver cancer cells. We demonstrate that HP treatment increased apoptosis, reduced cell viability, and reduced cell migration in Hep3B human liver cancer cells without affecting the normal liver cell line L02. We correlate these phenotypes with increased cellular ROS levels, upregulation of cleaved caspase 3 and Bad, and downregulation of antiapoptotic Bcl-2. HP treatment led to increased Akt and GSK-3β phosphorylation, with subsequent downregulation of β-catenin, suggesting β-catenin signaling modulation as a critical mechanism by which HP exhibits anticancer properties. Our findings suggest HP are of potential therapeutic interest for liver cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/33841802/

“Together, these data demonstrate that HP from hemp seed protein hydrolysates display anticancer properties. Increase in cellular ROS levels represents a crucial mechanism by which HP exerts its antiproliferative and proapoptotic activity and HP treatment modulates activity of the Akt/GSK/β‐catenin signaling pathway. Our findings suggest that HP represents a promising anticancer therapy in the context of liver cancer; further investigation of the anticancer properties of foodborne protein hydrolysates is warranted.”

https://onlinelibrary.wiley.com/doi/10.1002/fsn3.1976

Molecular Mechanism of Cannabinoids in Cancer Progression

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ijms-logo“Cannabinoids are a family of heterogeneous compounds that mostly interact with receptors eliciting several physiological effects both in the central and peripheral nervous systems and in peripheral organs. They exert anticancer action by modulating signaling pathways involved in cancer progression; furthermore, the effects induced by their use depend on both the type of tumor and their action on the components of the endocannabinoid system. This review will explore the mechanism of action of the cannabinoids in signaling pathways involved in cancer proliferation, neovascularisation, migration, invasion, metastasis, and tumor angiogenesis.”

https://pubmed.ncbi.nlm.nih.gov/33916164/

https://www.mdpi.com/1422-0067/22/7/3680

Cannabinoid Receptor Type-2 in B Cells Is Associated with Tumor Immunity in Melanoma

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cancers-logo“Agents targeting the endocannabinoid system (ECS) have gained attention as potential cancer treatments. Given recent evidence that cannabinoid receptor 2 (CB2R) regulates lymphocyte development and inflammation, we performed studies on CB2R in the immune response against melanoma. Analysis of The Cancer Genome Atlas (TCGA) data revealed a strong positive correlation between CB2R expression and survival, as well as B cell infiltration in human melanoma. In a murine melanoma model, CB2R expression reduced the growth of melanoma as well as the B cell frequencies in the tumor microenvironment (TME), compared to CB2R-deficient mice. In depth analysis of tumor-infiltrating B cells using single-cell RNA sequencing suggested a less differentiated phenotype in tumors from Cb2r-/- mice. Thus, in this study, we demonstrate for the first time a protective, B cell-mediated role of CB2R in melanoma. This gained insight might assist in the development of novel, CB2R-targeted cancer therapies.”

https://pubmed.ncbi.nlm.nih.gov/33923757/

“In this study we investigated the role of cannabinoid receptor 2 (CB2R) on immune cells in melanoma and found significantly improved overall survival in patients with high intra-tumoral CB2R gene expression. In human melanoma, CB2R is predominantly expressed in B cells, as shown using a previously published single-cell RNA sequencing (scRNA-seq) dataset and by performing RNAscope. In a murine melanoma model, tumor growth was enhanced in CB2R-deficient mice. In-depth analysis of tumor-infiltrating lymphocytes using scRNA-seq showed less differentiated B cells in CB2R-deficient tumors, favoring the induction of regulatory T cells (Treg) and an immunosuppressive tumor microenvironment. Taken together, these data indicate a central role of CB2R on B cells in regulating tumor immunity. These results contribute to the understanding of the role of CB2R in tumor immunity and facilitate the development of new CB2R-targeted anti-cancer drugs.”

https://www.mdpi.com/2072-6694/13/8/1934

Cannabinoids pharmacological effects are beyond the palliative effects: CB2 cannabinoid receptor agonist induced cytotoxicity and apoptosis in human colorectal cancer cells (HT-29)

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SpringerLink“Colorectal cancer (CRC) is between the top three occurring cancers worldwide. The anticancer effects of Cannabinoid receptor 2 (CB2) agonist (GW833972A) in the presence and absence of its inverse agonist (SR144528) on Human colorectal adenocarcinoma cells (HT-29) was investigated. Following cell viability assays on HT-29 and HFF cells, the molecular mechanism(s) of cytotoxicity and apoptotic pathways of cell death were analyzed. The anticancer effects of CB2 agonist were measured with tumor cell migration and colony-forming assays. Real-time PCR and Western blotting techniques were used to examine any alterations in the expression of apoptotic genes. A concentration and time-dependent cytotoxicity of CB2 agonist with IC50 value of 24.92 ± 6.99 μM was obtained. The rate of lipid peroxidation was elevated, while the TNF-α concentration was declined, significantly (p < 0.05). CB2 agonist (50 μM) reduced the colony-forming capability by 83% and tumor cell migration by 50%. Apoptotic effects of CB2 agonist were revealed with the increase of apoptotic cells in Acridine orange/Ethidium bromide staining, clear DNA fragmentation, pro-apoptotic genes and proteins upregulation (Caspase-3 and p53), and significant downregulation of anti-apoptotic Bcl-2. All assessments demonstrated that CB2 agonist-induced effects were reversed by CB2 inverse agonist. These data suggest that CB2 agonists at micro-molar concentrations might be considered in the CRC treatment, and their effectiveness attributes to the apoptosis induction via upregulation of caspase-3 and p53 and downregulation of Bcl-2.”

https://pubmed.ncbi.nlm.nih.gov/33886060/

https://link.springer.com/article/10.1007/s11010-021-04158-6

Specific Compositions of Cannabis sativa Compounds Have Cytotoxic Activity and Inhibit Motility and Colony Formation of Human Glioblastoma Cells In Vitro

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cancers-logo“Glioblastoma multiforme (GBM) is the most lethal subtype of glioma. Cannabis sativa is used for the treatment of various medical conditions. Around 150 phytocannabinoids have been identified in C. sativa, among them Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) that trigger GBM cell death. However, the optimal combinations of cannabis molecules for anti-GBM activity are unknown. Chemical composition was determined using high-performance liquid chromatography (HPLC) and gas chromatography mass spectrometry (GC/MS). Cytotoxic activity was determined by XTT and lactate dehydrogenase (LDH) assays and apoptosis and cell cycle by fluorescence-activated cell sorting (FACS). F-actin structures were observed by confocal microscopy, gene expression by quantitative PCR, and cell migration and invasion by scratch and transwell assays, respectively. Fractions of a high-THC cannabis strain extract had significant cytotoxic activity against GBM cell lines and glioma stem cells derived from tumor specimens. A standard mix (SM) of the active fractions F4 and F5 induced apoptosis and expression of endoplasmic reticulum (ER)-stress associated-genes. F4 and F5 inhibited cell migration and invasion, altered cell cytoskeletons, and inhibited colony formation in 2 and 3-dimensional models. Combinations of cannabis compounds exert cytotoxic, anti-proliferative, and anti-migratory effects and should be examined for efficacy on GBM in pre-clinical studies and clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/33916466/

“Glioblastoma multiforme (GBM) is the most frequent, invasive, and lethal subtype of glioma brain tumors. Cannabis is commonly used for medical treatment, and individual phytocannabinoids have been shown to trigger GBM cell death. However, cannabis contains hundreds of different compounds, and the optimal combinations of molecules with anti-GBM activity are unknown. Here, we identified fractions from a cannabis strain that substantially reduced human GBM cell viability and motility. The fractions also reduced the ability of GBM cells to form colonies in 2 and 3-dimensional models, suggesting that the cannabis treatments may have the potential for preventing the formation of GBM neurospheres associated with the high resistance to current therapies. Importantly, these compounds also induced cell death in glioma stem cells derived from tumor specimens. The effectiveness of the fractions and combinations of cannabis compounds should be examined in GBM pre-clinical studies and clinical trials.”

https://www.mdpi.com/2072-6694/13/7/1720