A Novel Mechanism of Cannabidiol in Suppressing Hepatocellular Carcinoma by Inducing GSDME Dependent Pyroptosis

Frontiers in Cell and Developmental Biology - Institut de Myologie“Cannabidiol (CBD), a phytochemical derived from Cannabis sativa L., has been demonstrated to exhibit promising anti-tumor properties in multiple cancer types. However, the effects of CBD on hepatocellular carcinoma (HCC) cells remain unknown. We have shown that CBD effectively suppresses HCC cell growth in vivo and in vitro, and induced HCC cell pyroptosis in a caspase-3/GSDME-dependent manner. We further demonstrated that accumulation of integrative stress response (ISR) and mitochondrial stress may contribute to the initiation of pyroptotic signaling by CBD. Simultaneously, CBD can repress aerobic glycolysis through modulation of the ATF4-IGFBP1-Akt axis, due to the depletion of ATP and crucial intermediate metabolites. Collectively, these observations indicate that CBD could be considered as a potential compound for HCC therapy.”

https://pubmed.ncbi.nlm.nih.gov/34350183/

“Hepatocellular carcinoma (HCC) is an extremely malignant cancer, accounting for almost 95% of primary liver cancer cases. Cannabidiol (CBD), a phytochemical derived from Cannabis sativa L., has been shown to have anti-tumor activity and to be a potential compound for tumor therapy. Previous studies have demonstrated that CBD treatment could effectively induce cell apoptosis in tumor cells. In this study, we have shown that CBD can effectively suppress HCC cell growth both in vitro and in vivo, which was similar to the anti-tumor activity of CBD observed in other cancer types. In summary, a mechanistic model of CBD anti-tumor activity in HCC cell pyroptosis and growth was demonstrated. All the observations described herein reveal a novel mechanism of the anti-tumor activity of CBD in HCC cells, suggesting that CBD could be considered as a promising compound for HCC therapy.”

https://www.frontiersin.org/articles/10.3389/fcell.2021.697832/full

Combination therapy with cannabidiol and chemotherapeutics in canine urothelial carcinoma cells

“Background: Canine urothelial carcinoma is the most common form of canine bladder cancer. Treatment with chemotherapy has variable response rates leading to most dogs succumbing to their disease within a year. Cannabidiol is an emerging treatment within the field of oncology. In reported in vivo studies, cannabidiol has induced apoptosis, reduced cell migration, and acted as a chemotherapy sensitizer in various human tumor types. The aim of this study was to characterize the effects of cannabidiol on canine urothelial carcinoma cell viability and apoptosis as both a single agent and in combination with chemotherapy in vitro.

Results: Cannabidiol reduced cell viability and induced apoptosis in canine urothelial cells as determined by crystal violet viability assay and annexin V/propidium iodide flow cytometry. Furthermore, combinations of cannabidiol with mitoxantrone and vinblastine chemotherapy yielded significantly reduced cell viability and increased apoptosis compared to single agent treatment alone. The drug interactions were deemed synergistic based on combination index calculations. Conversely, the combination of cannabidiol and carboplatin did not result in decreased cell viability and increased apoptosis compared to single agent treatment. Combination index calculations suggested an antagonistic interaction between these drugs. Finally, the combination of the non-steroidal anti-inflammatory drug piroxicam with cannabidiol did not significantly affect cell viability, although, some cell lines demonstrated decreased cell viability when mitoxantrone was combined with piroxicam.

Conclusions: Cannabidiol showed promising results as a single agent or in combination with mitoxantrone and vinblastine for treatment of canine urothelial carcinoma cells. Further studies are justified to investigate whether these results are translatable in vivo.”

https://pubmed.ncbi.nlm.nih.gov/34352013/

“Cannabidiol (CBD) is a phytocannabinoid derived from the Cannabis sativa plant with well-documented analgesic, anti-inflammatory, and anxiolytic effects. This study determined that CBD treatment reduced viability and induced cell death in canine urothelial carcinoma cells in vitro. Taken together, these results suggest that CBD may be a potential treatment for use in combination with chemotherapeutic agents to improve canine UC carcinoma response rates and survival.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255591

 

The Pharmacological Effects of Plant-Derived versus Synthetic Cannabidiol in Human Cell Lines

/WebMaterial/ShowPic/1344608“Introduction: Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced. The aim of this study was to compare the in vitro effects of purified natural and synthetic CBD to establish any pharmacological differences or superiority between sources. 

Conclusion: Our results suggest that there is no pharmacological difference in vitro in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD. The purity and reliability of CBD samples, as well as the ultimate pharmaceutical preparation, should all be considered above the starting source of CBD in the development of new CBD medicines.

This study demonstrates for the first time that the anticancer, neuroprotective, and intestinal barrier protective properties of purified CBD are similar regardless of the source from which CBD is derived. From a pharmacological perspective, where a molecular target is implicated (i.e., 5HT1A in stroke and CB1 in gut permeability), the effects of CBD were similar. This suggests that any beneficial effects that could be achieved in a clinical setting for purified CBD are likely to be similar at a pharmacodynamic level.”

https://www.karger.com/Article/FullText/517120

“Study finds no in-vitro pharmacological difference in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD”

https://www.streetinsider.com/Globe+Newswire/Artelo+Biosciences+Announces+Publication+of+Study+Results+Comparing+the+Pharmacological+Effects+of+Plant-Derived+Versus+Synthetic+Cannabidiol+in+Human+Cell+Lines/18767297.html

Cannabidiol Loaded Extracellular Vesicles Sensitize Triple-Negative Breast Cancer to Doxorubicin in both in-vitro and in vivo Models Running Title: Formulation and anti-cancer potential of CBD loaded hUCMSC-derived Extracellular Vesicles in TNBC

International Journal of Pharmaceutics“Extracellular Vesicles (EVs) were isolated from human umbilical cord mesenchymal stem cells (hUCMSCs) and were further encapsulated with cannabidiol (CBD) through sonication method (CBD EVs). CBD EVs displayed an average particle size of 114.1±1.02 nm, zeta potential of -30.26±0.12 mV, entrapment efficiency of 92.3±2.21% and stability for several months at 4 °C. CBD release from the EVs was observed as 50.74±2.44% and 53.99±1.4% at pH 6.8 and pH 7.4, respectively after 48 h. Ourin-vitrostudies demonstrated that CBD either alone or in EVs form significantly sensitized MDA-MB-231 cells to doxorubicin (DOX) (*P<0.05). Flow cytometry and migration studies revealed that CBD EVs either alone or in combination with DOX induced G1 phase cell cycle arrest and decreased migration of MDA-MB-231 cells, respectively. CBD EVs and DOX combination significantly reduced tumor burden (***P<0.001) in MDA-MB-231 xenograft tumor model. Western blotting and immunocytochemical analysis demonstrated that CBD EVs and DOX combination decreased the expression of proteins involved in inflammation, metastasis and increased the expression of proteins involved in apoptosis. CBD EVs and DOX combination will have profound clinical significance in not only decreasing the side effects but also increasing the therapeutic efficacy of DOX in TNBC.”

https://pubmed.ncbi.nlm.nih.gov/34324983/

https://www.sciencedirect.com/science/article/abs/pii/S0378517321007493?via%3Dihub

KY Hemp-induced Modulation of Ovarian Cancer Cell Metastasis

“Our laboratory is interested in searching for a new plant-based therapeutics to treat ovarian cancer.

We are interested in studying anti-cancer effects of KY grown hemp as a potential candidate drug.

Marijuana and hemp belong to the same genus and species. However, they are different in cannabidiol (CBD) and tetrahydrocannabinol (THC) content.

Both CBD and THC are therapeutically beneficial. Hemp is harmless and non-addictive.

Major objective of this study is to investigate whether KY hemp extract can modulate the metastasis of ovarian cancer.

Based on the data here we conclude that KY hemp has significant anti-metastatic properties against ovarian cancer.”

https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.2018.32.1_supplement.667.7

Searching for a New Anti-Cancer Drug: Investigation of KY Hemp-Induced Apoptosis in Ovarian Cancer Cells

“Marijuana (cannabis sativa) is a schedule 1 drug that has been recently approved by some states in the US for its therapeutic benefit.

Although there are a few reports about its anti-cancer potential, currently it has been used mainly for treatment-resistant epilepsy and to alleviate pain.

Hemp, which belongs to the same genus and species as marijuana, shows similar therapeutic benefits without addictive potential.

Our laboratory is interested in examining for unconventional therapies for ovarian cancer.

The main objective of the current study is to investigate hemp-induced modulation of A2780 ovarian cancer cell apoptosis.

Based on the data here we conclude that KY hemp has anti-cancer potential against ovarian cancer.”

https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.2018.32.1_supplement.616.1

Cannabinoids and their derivatives in struggle against melanoma

SpringerLink“Melanoma is one of the most aggressive malignances in human. Recently developed therapies improved overall survival rate, however, the treatment of melanoma still remains a challenging issue.

This review attempts to summarize recent advances in studies on cannabinoids used in the setting of melanoma treatment.

Conclusions after analysis of available data suggest that cannabinoids limit number of metastasis, and reduce growth of melanoma. The findings indicate that cannabinoids induce apoptosis, necrosis, autophagy, cell cycle arrest and exert significant interactions with tumor microenvironment.

Cannabinoids should be rather considered as a part of multi-targeted anti-tumor therapy instead of being standalone agent. Moreover, cannabinoids are likely to improve quality of life in patients with cancer, due to different supportive effects, like analgesia and/or anti-emetic effects.

In this review, it was pointed out that cannabinoids may be potentially useful in the melanoma therapy. Nevertheless, due to limited amount of data, great variety of cannabinoids available and lack of clinical trials, further studies are required to determine an exact role of cannabinoids in the treatment of melanoma.”

https://pubmed.ncbi.nlm.nih.gov/34264513/

“The endocannabinoid system is dysregulated in numerous pathological conditions, including malignancies. Recently, cannabinoids have received increasing amount of interest in the setting of treatment of various cancers.  Cannabinoids seem to be promising agents in the setting of melanoma treatment. In the case of melanoma, most important actions of cannabinoids described so far are decrease of cells viability by increase of apoptosis, necrosis and cell cycle arrest. Moreover, cannabinoids slow down disease progress by reduction of metastasis and tumor vascularization. Due to large variety of cannabinoids, there are many potential derivatives, which may be found useful in the therapy of melanoma.”

https://link.springer.com/article/10.1007%2Fs43440-021-00308-1

Cannabinoids in the landscape of cancer

SpringerLinkCannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. There is a growing body of evidence from cell culture and animal studies in support of cannabinoids possessing anticancer properties.

Method: A database search of peer reviewed articles published in English as full texts between January 1970 and April 2021 in Google Scholar, MEDLINE, PubMed and Web of Science was undertaken. References of relevant literature were searched to identify additional studies to construct a narrative literature review of oncological effects of cannabinoids in pre-clinical and clinical studies in various cancer types.

Results: Phyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivo. However, these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets. The mechanism of action of synthetic cannabinoids, (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has mainly been described via the traditional cannabinoid receptors; CB1 and CB2, but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2.

Conclusion: Cannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs. These effects have occurred through various receptors and ligands and modulation of signalling pathways involved in hallmarks of cancer pathology. There is a need for further studies to characterise its mode of action at the molecular level and to delineate efficacious dosage and route of administration in addition to synergistic regimes.”

https://pubmed.ncbi.nlm.nih.gov/34259916/

“Since time immemorial, the Cannabis plant has been used as a source of fibre, herbal remedy, medicinal and religious purposes. In the mid-nineteenth century, O’Shaughnessy and Moreau reported positive effects of cannabis on muscle spasms, vomiting, convulsions, rheumatism, tetanus, and rabies. However, during the twentieth century, its utilisation in Western medicine started to decline as a result of political prejudices and economic interests rather than scientific or medical reasons.

Plant-based, endogenous and synthetic cannabinoid compounds have shown merits in not only alleviating the unwanted side effects of antineoplastic drug regiments, but have also shown promising evidence in decreasing tumour burden, and one in vivo study so far concludes increasing survival rates in mice. Various extracted forms of cannabinoids from C. sativa have shown varying cytotoxic effects which should be explored in more detail in future studies as majority of the evidence originates from studies investigating mainly ∆9-THC and CBD’s actions.”

https://link.springer.com/article/10.1007/s00432-021-03710-7

New Insights on Hemp Oil Enriched in Cannabidiol: Decarboxylation, Antioxidant Properties and In Vitro Anticancer Effect

antioxidants-logo“This study aimed to obtain and characterize extracted hemp oil enriched in cannabidiol (CBD) by decarboxylation of cannabidiolic acid (CBDA) and to give new insights into its antioxidant and anticancer effects.

CBD-enriched oil promoted NHDF proliferation at up to 15 µg CBD/mL, while inducing apoptosis and ROS production and modulating antioxidant enzymes’ gene expression in cancer cells, being selective for osteosarcoma cells, and induced apoptosis by p53- and ROS-independent mechanisms.

CBD-enriched hemp oil demonstrated antioxidant properties in oxidative conditions and promoted normal fibroblasts’ proliferation, while inducing apoptosis and ROS production in cancer cells.”

https://pubmed.ncbi.nlm.nih.gov/34067035/

https://www.mdpi.com/2076-3921/10/5/738

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

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