Cannabidiol converts NFκB into a tumor suppressor in glioblastoma with defined antioxidative properties

ISNO: Indian Society of Neuro-Oncology “The transcription factor NFκB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFκB activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive.

Methods: In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFκB 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.

Results: We found that CBD promotes DNA binding of the NFκB subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which 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 predictive biomarker for CBD-sensitive tumors.

Conclusions: This evidence demonstrates how a clinically approved drug can convert NFκB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.”

https://pubmed.ncbi.nlm.nih.gov/33864076/

https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noab095/6231710

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Cannabinoid Quinones-A Review and Novel Observations

molecules-logo“A cannabinoid anticancer para-quinone, HU-331, which was synthesized by our group five decades ago, was shown to have very high efficacy against human cancer cell lines in-vitro and against in-vivo grafts of human tumors in nude mice. The main mechanism was topoisomerase IIα catalytic inhibition. Later, several groups synthesized related compounds. In the present presentation, we review the publications on compounds synthesized on the basis of HU-331, summarize their published activities and mechanisms of action and report the synthesis and action of novel quinones, thus expanding the structure-activity relationship in these series.”

https://pubmed.ncbi.nlm.nih.gov/33801057/

https://www.mdpi.com/1420-3049/26/6/1761

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Human laryngeal squamous cell carcinoma cell line release of endogenous anandamide and 2-arachidonoylglycerol, and their antiproliferative effect via exogenous supplementation: an in vitro study

SpringerLink“The level of the major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are altered in several types of carcinomas, and are known to regulate tumor growth. Thusly, this study hypothesized that the HEp-2 human laryngeal squamous cell carcinoma (LSCC) cell line releases AEA and 2-AG, and aimed to determine if their exogenous supplementation has an anti-proliferative effect in vitro.

In this in vitro observational study a commercial human LSCC cell line (HEp-2) was used to test for endogenous AEA and 2-AG release via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The anti-proliferative effect of AEA and 2-AG supplementation was evaluated via WST-1 proliferation assay. It was observed that the HEp-2 LSCC cell line released AEA and 2-AG; the median quantity of AEA released was 15.69 ng mL-1 (range: 14.55-15.95 ng mL-1) and the median quantity of 2-AG released was 2.72 ng -1 (range: 2.67-2.74 ng mL-1). Additionally, both AEA and 2-AG exhibited an anti-proliferative effect. The anti-proliferative effect of 2-AG was stronger than that of AEA. These findings suggest that AEA might function via a CB1 receptor-independent pathway and that 2-AG might function via a CB2-dependent pathway.

The present findings show that the HEp-2 LSCC cell line releases the major endocannabinoids AEA and 2-AG, and that their supplementation inhibits tumor cell proliferation in vitro. Thus, cannabinoid ligands might represent novel drug candidates for laryngeal cancers, although functional in vivo studies are required in order to validate their potency.”

https://pubmed.ncbi.nlm.nih.gov/33797678/

https://link.springer.com/article/10.1007/s10561-021-09917-9

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Different Cannabis sativa Extraction Methods Result in Different Biological Activities against a Colon Cancer Cell Line and Healthy Colon Cells

plants-logo“Cannabis sativa is one of the oldest medicinal plants used by humans, containing hundreds of bioactive compounds. The biological effects and interplay of these compounds are far from fully understood, although the plant’s therapeutic effects are beyond doubt.

Extraction methods for these compounds are becoming an integral part of modern Cannabis-based medicine. Still, little is known about how different methods affect the final composition of Cannabis extracts and thus, their therapeutic effects.

In this study, different extraction methods were tested, namely maceration, Soxhlet, ultrasound-assisted extraction (UAE), and supercritical CO2 extraction methods. The obtained extracts were evaluated for their cannabinoid content, antioxidant properties, and in vitro bioactivity on human colon cancer and healthy colon cells.

Our data suggest that Cannabis extracts, when properly prepared, can significantly decrease cancer cell viability while protecting healthy cells from cytotoxic effects.

However, post-processing of extracts poses a significant limitation in predicting therapeutic response based on the composition of the crude extract, as it affects not only the actual amounts of the respective cannabinoids but also their relative ratio to the primary extracts. These effects must be carefully considered in the future preparations of new therapeutic extracts.”

https://pubmed.ncbi.nlm.nih.gov/33802757/

https://www.mdpi.com/2223-7747/10/3/566

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Molecular Mechanism of Autophagy and Its Regulation by Cannabinoids in Cancer

cancers-logo“Autophagy is a “self-degradation” process whereby malfunctioned cytoplasmic constituents and protein aggregates are engulfed by a vesicle called the autophagosome, and subsequently degraded by the lysosome. Autophagy plays a crucial role in sustaining protein homeostasis and can be an alternative source of energy under detrimental circumstances. Studies have demonstrated a paradoxical function for autophagy in cancer, displaying both tumour suppressive and tumour promotive roles. In early phases of tumour development autophagy promotes cancer cell death. In later phases, autophagy enables cancer cells to survive and withstand therapy.

Cannabinoids, which are derivatives of the Cannabis sativa L. plant, have shown to be associated with autophagy induction in cells. There is an emerging interest in studying the signalling pathways involved in cannabinoid-induced autophagy and their potential application in anticancer therapies. In this review, the molecular mechanisms involved in the autophagy degradation process will be discussed. This review also highlights a role for autophagy in cancer progression, with cannabinoid-induced autophagy presenting a novel strategy for anticancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/33802014/

“This review examines the complex function of autophagy in malignancy and explores its regulation by cannabinoids in different cancers. Autophagy is an important process in the maintenance of cellular homeostasis, through the degradation and recycling of cytoplasmic constituents. The action of autophagy is highly dependent on tumour stage and type and the receptors with which ligands interact. Cannabinoids are growingly being acknowledged for their anticancer activities and are known to stimulate several mechanisms such as apoptosis and autophagy. Better understanding the mechanism of action behind autophagy and its regulation by cannabinoids will allow the development of novel cancer therapeutics.”
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THC Reduces Ki67-Immunoreactive Cells Derived from Human Primary Glioblastoma in a GPR55-Dependent Manner

cancers-logo

“Glioblastoma (GBM) is the most frequent malignant tumor of the central nervous system in humans with a median survival time of less than 15 months.

9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best-characterized components of Cannabis sativa plants with modulating effects on cannabinoid receptors 1 and 2 (CB1 and CB2) and on orphan receptors such as GPR18 or GPR55. Previous studies have demonstrated anti-tumorigenic effects of THC and CBD in several tumor entities including GBM, mostly mediated via CB1 or CB2.

In this study, we investigated the non-CB1/CB2 effects of THC on the cell cycle of GBM cells isolated from human tumor samples.

Cell cycle entry was measured after 24 h upon exposure by immunocytochemical analysis of Ki67 as proliferation marker. The Ki67-reducing effect of THC was abolished in the presence of CBD, whereas CBD alone did not cause any changes. To identify the responsible receptor for THC effects, we first characterized the cells regarding their expression of different cannabinoid receptors: CB1, CB2, GPR18, and GPR55. Secondly, the receptors were pharmacologically blocked by application of their selective antagonists AM281, AM630, O-1918, and CID16020046 (CID), respectively. All examined cells expressed the receptors, but only in presence of the GPR55 antagonist CID was the THC effect diminished. Stimulation with the GPR55 agonist lysophosphatidylinositol (LPI) revealed similar effects as obtained for THC. The LPI effects were also inhibited by CBD and CID, confirming a participation of GPR55 and suggesting its involvement in modifying the cell cycle of patient-derived GBM cells.”

https://pubmed.ncbi.nlm.nih.gov/33802282/

“Glioblastoma (GBM) is the most frequent primary brain tumor entity with poor prognosis and resistance to current standard therapies. Cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD) are discussed as promising compounds for individualized treatment, as they exert anti-tumor effects by binding to cannabinoid-specific receptors. However, their pharmacology is highly diverse and complex. The present study was designed to verify (1) whether cannabinoids show even any effect in GBM cells derived from primary human tumor samples and (2) to identify the receptor responsible for those effects. Our findings revealed that THC reduces the number of Ki67 immunoreactive nuclei, a cell cycle marker through the orphan cannabinoid receptor GPR55. The data suggest a therapeutic potential of cannabinoids in those GBM with functional and responsive GPR55.”

https://www.mdpi.com/2072-6694/13/5/1064

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Efficacy of cannabinoids against glioblastoma multiforme: A systematic review

Phytomedicine

“INTRODUCTION

: 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.

OBJECTIVE

: 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.

METHOD

: 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.

RESULTS

: 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.

CONCLUSION

: 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.”

HTTPS://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/ABS/PII/S0944711321000751

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The effect of cannabis in the treatment of Hodgkin’s lymphoma in a pregnant patient – extensive case report and literature review

pubmed logo“Purpose: Hodgkin lymphoma (HL) is the fourth most frequent cancer diagnosis among pregnant females. A multidisciplinary team is mandatory to obtain the best treatment and prognosis for the mother and for the baby. Here, we present the case of a patient diagnosed with HL and its evolution during 2 pregnancies.

Case presentation: Herein we present the case of a 21-year-old female Caucasian patient, with free history, diagnosed with HL stage IIB. The patient started first line chemotherapy and radiotherapy, with incomplete remission. She refused any other treatment. Five years later, the patient became pregnant and was offered chemotherapy in the 2nd trimester of pregnancy, that she refused, and delivered by C-section at 37 weeks. In the same year, the patient became pregnant again and was proposed termination of pregnancy, that she also refused. The MRI scan revealed progression of HL and she was admitted in the hospital several times for altered general condition, respiratory infections and increased need of painkillers including opioids.

At 26 weeks of pregnancy, the patient began on her own a treatment with pure cannabis. Her pain and general status got better and the tumor tissue decreased.

She delivered by C-section at 34 weeks a boy that presented in the first 24 h postpartum a withdrawal syndrome and intestinal invagination, requiring care in NICU and surgery with bowel resection.

Conclusion: Therefore, we can conclude that cannabis could be part of oncological treatment. No other case like this, as far as we know, has been previously reported.”

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Unveiling the mechanism of action behind the anti-cancer properties of cannabinoids in ER + breast cancer cells: impact on aromatase and steroid receptors

The Journal of Steroid Biochemistry and Molecular Biology“Breast cancer is the leading cause of cancer-related death in women worldwide. In the last years, cannabinoids have gained attention in the clinical setting and clinical trials with cannabinoid-based preparations are underway. However, contradictory anti-tumour properties have also been reported. Thus, the elucidation of the molecular mechanisms behind their anti-tumour efficacy is crucial to better understand its therapeutic potential.

Considering this, our work aims to clarify the molecular mechanisms underlying the anti-cancer properties of the endocannabinoid anandamide (AEA) and of the phytocannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), in estrogen receptor-positive (ER+) breast cancer cells that overexpress aromatase (MCF-7aro). Their in vitro effects on cell proliferation, cell death and activity/expression of aromatase, ERα, ERβ and AR were investigated.

Our results demonstrated that cannabinoids disrupted MCF-7aro cell cycle progression. Unlike AEA and THC that induced apoptosis, CBD triggered autophagy to promote apoptotic cell death. Interestingly, all cannabinoids reduced aromatase and ERα expression levels in cells. On the other hand, AEA and CBD not only exhibited high anti-aromatase activity but also induced up-regulation of ERβ. Therefore, all cannabinoids, albeit by different actions, target aromatase and ERs, impairing, in that way, the growth of ER+ breast cancer cells, which is dependent on estrogen signalling.

As aromatase and ERs are key targets for ER+ breast cancer treatment, cannabinoids can be considered as potential and attractive therapeutic compounds for this type of cancer, being CBD the most promising one. Thus, from an in vitro perspective, this work may contribute to the growing mass of evidence of cannabinoids and cannabinoids-based medicines as potential anti-cancer drugs.”

https://pubmed.ncbi.nlm.nih.gov/33722705/

“AEA and THC induce apoptosis in ER+ breast cancer cells, while CBD trigger autophagy to promote apoptosis. AEATHC and CBD impair growth of ER+ breast cancer cells, by disrupting cycle progression. AEATHC and CBD affect aromatase and ERα expression levels in ER+ breast cancer cells. AEA and CBD strongly inhibited aromatase activity and up-regulated ERβ levels. Cannabinoids are considered potential therapeutic compounds for ER+ breast cancer, being CBD the most promising one.”

https://www.sciencedirect.com/science/article/abs/pii/S0960076021000698?via%3Dihub

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Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management

 Journal of Cancer Research and Therapeutics“Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug. Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol. Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system. Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss. THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals). Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits. The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.”

https://pubmed.ncbi.nlm.nih.gov/33723124/

“Specific targeting of cannabinoid receptors can be used to manage severe side effects during chemotherapy, palliative care, and overall cancer management. Furthermore, research evidences on cannabinoids have suggested tumor inhibiting and suppressing properties which warrant reconsidering legality of the substance. Studies on CB1 and CB2 receptors, in case of cancers, have demonstrated the psychoactive constituents of cannabinoids to be potent against tumor growth. Interestingly, studies have also shown that activation of CB1 and CB2 cannabinoid receptors by their respective synthetic agonists tends to limit human cancer cell growth, suggesting the role of the endocannabinoid system as a novel target for treatment of cancers.”

https://www.cancerjournal.net/article.asp?issn=0973-1482;year=2021;volume=17;issue=1;spage=1;epage=9;aulast=Shah

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