“Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME.

Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive.

This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.”

https://pubmed.ncbi.nlm.nih.gov/33255584/

“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449

https://www.mdpi.com/1422-0067/21/23/8929

“In the last decade the use of medical cannabis (MC) for palliative cancer treatment has risen. However, the choice between products is arbitrary and most patients are using Tetrahydrocannabinol (THC)-dominant cannabis products.

In this study, we aimed to assess the short-term outcomes of MC treatment prescribed by oncologists in relation to the type of cannabis they receive.

A comparative analysis was used to assess the differences in treatment effectiveness and safety between THC-dominant (n = 56, 52%), cannabidiol (CBD)-dominant (n = 19, 18%), and mixed (n = 33, 30%) MC treatments. Oncology patients (n = 108) reported on multiple symptoms in baseline questionnaires, initiated MC treatment, and completed a one-month follow-up.

Most parameters improved significantly from baseline, including pain intensity, affective and sensory pain, sleep quality and duration, cancer distress, and both physical and psychological symptom burden. There was no significant difference between the three MC treatments in the MC-related safety profile. Generally, there were no differences between the three MC treatments in pain intensity and in most secondary outcomes.

Unexpectedly, CBD-dominant oil treatments were similar to THC-dominant treatments in their beneficial effects for most secondary outcomes. THC-dominant treatments showed significant superiority in their beneficial effect only in sleep duration compared to CBD-dominant treatments.

This work provides evidence that, though patients usually consume THC-dominant products, caregivers should also consider CBD-dominant products as a useful treatment for cancer-related symptoms.”

https://pubmed.ncbi.nlm.nih.gov/33265945/

https://www.mdpi.com/1424-8247/13/12/435

 “Melanoma causes the highest number of skin cancer-related deaths worldwide. New treatment methods are essential for the management of this life-threatening disease.

Aims: In this study, we investigated the efficacy of a standardized Cannabis sativa extract alone or in combination with single radiation dose (6 Gy) in B16F10 mouse melanoma cells in an extract dose-dependent manner.

Results: Administration of the extract alone or alongside radiation substantially inhibited melanoma cell viability and proliferation in the extract dose response-dependent manner. The inhibition of melanoma cell viability was paralleled by an increase in necrosis but not apoptosis when melanoma cells were treated with the extract alone. Radiation alone did not have any antiproliferative effects, and radiation also did not synergize antiproliferative effects of the extract when the extract and radiation were combined.

Conclusion: Our data suggest that C. sativa extract may have significant health and physiological implications for the treatment of melanoma. The results of this study also indicate that B16F10 mouse melanoma cells are radioresistant. Taken together, these findings may lead to the identification of new therapeutic strategy for the management of melanoma.”

https://pubmed.ncbi.nlm.nih.gov/33342819/

“This study provides the first evidence of antitumor effects of C. sativa extract, when administered alone or in combination with radiation, to mouse melanoma cells in vitro. Our results may verify the value of C. sativa extract for the treatment of melanoma and may complement the therapeutic profile of C. sativa extracts administration in the future.”

https://www.cancerjournal.net/article.asp?issn=0973-1482;year=2020;volume=16;issue=6;spage=1495;epage=1499;aulast=Naderi

“Anticancer activity of different phenols is documented, but underlying mechanisms remain elusive. Recently, we have shown that cannabidiol kills the cells of acute lymphoblastic leukemia (ALL) by a direct interaction with mitochondria, with their consequent dysfunction.

In the present study, cytotoxic effects of several phenolic compounds against human the T-ALL cell line Jurkat were tested by means of resazurin-based metabolic assay. To unravel underlying mechanisms, mitochondrial membrane potential (∆Ψ_m) and [Ca²⁺]_m measurements were undertaken, and reactive oxygen species generation and cell death were evaluated by flow cytometry.

Three out of eight tested phenolics, cannabidiol, curcumin and quercetin, which displayed a significant cytotoxic effect, also dissipated the ∆Ψ_m and induced a significant [Ca²⁺]_m increase, whereas inefficient phenols did not.

Dissipation of the ∆Ψ_m by cannabidiol was prevented by cyclosporine A and reverted by Ru360, inhibitors of the permeation transition pore and mitochondrial Ca²⁺ uniporter, respectively. Ru360 prevented the phenol-induced [Ca²⁺]_m rise, but neither cyclosporine A nor Ru360 affected the curcumin- and quercetin-induced ∆Ψ_m depolarization. Ru360 impeded the curcumin- and cannabidiol-induced cell death.

Thus, all three phenols exert their antileukemic activity via mitochondrial Ca²⁺ overload, whereas curcumin and quercetin suppress the metabolism of leukemic cells by direct mitochondrial uncoupling.”

https://pubmed.ncbi.nlm.nih.gov/33379175/

https://www.mdpi.com/1422-0067/22/1/204

“Gynaecological cancers can be primary neoplasms, originating either from the reproductive tract or the products of conception, or secondary neoplasms, representative of metastatic disease. For some of these cancers, the exact causes are unknown; however, it is recognised that the precise aetiopathogeneses for most are multifactorial and include exogenous (such as diet) and endogenous factors (such as genetic predisposition), which mutually interact in a complex manner.

One factor that has been recognised to be involved in the pathogenesis and progression of gynaecological cancers is the endocannabinoid system (ECS). The ECS consists of endocannabinoids (bioactive lipids), their receptors, and metabolic enzymes responsible for their synthesis and degradation. In this review, the impact of plant-derived (Cannabis species) cannabinoids and endocannabinoids on gynaecological cancers will be discussed within the context of the complexity of the proteins that bind, transport, and metabolise these compounds in reproductive and other tissues. In particular, the potential of endocannabinoids, their receptors, and metabolic enzymes as biomarkers of specific cancers, such as those of the endometrium, will be addressed. Additionally, the therapeutic potential of targeting selected elements of the ECS as new action points for the development of innovative drugs will be presented.”

https://pubmed.ncbi.nlm.nih.gov/33375539/

“Cancers of the female reproductive system are common and are responsible for a large number of deaths in women. The exact reasons why some of these cancers occur are unknown. It is, however, known that for most of these cancers, several factors interact for them to happen. These interactions involve factors external and internal to the woman. An understanding of some of the internal factors involved in how these cancers arise will not only help drive preventive strategies, but will speed the development of new treatment approaches.

The endocannabinoid system is a family including chemicals (known as endocannabinoids) produced in the body that are similar to those derived from the cannabis plant. This system, which is widely distributed in the body, has been shown to be involved in various functions. Its disruption has been shown to lead to various diseases, one of which is cancer. In this review, we summarise current knowledge of this system, its various constituents, and how they are involved in reproductive events and their pathologies, especially cancers. Furthermore, we discuss the role of the endocannabinoid system in these cancers and how targeting it could lead to new approaches to diagnosis and treatment of cancers of the female reproductive system.”

https://www.mdpi.com/2072-6694/13/1/37

“Recently, there has been a growing interest in the medical applications of Cannabis plants. They owe their unique properties to a group of secondary metabolites known as phytocannabinoids, which are specific for this genus. Phytocannabinoids, and cannabinoids generally, can interact with cannabinoid receptors being part of the endocannabinoid system present in animals. Over the years a growing body of scientific evidence has been gathered, suggesting that these compounds have therapeutic potential.

In this article, we review the classification of cannabinoids, the molecular mechanisms of their interaction with animal cells as well as their potential application in the treatment of human diseases. Specifically, we focus on the research concerning the anticancer potential of cannabinoids in preclinical studies, their possible use in cancer treatment and palliative medicine, as well as their influence on the immune system. We also discuss their potential as therapeutic agents in infectious, autoimmune, and gastrointestinal inflammatory diseases.

We postulate that the currently ongoing and future clinical trials should be accompanied by research focused on the cellular and molecular response to cannabinoids and Cannabis extracts, which will ultimately allow us to fully understand the mechanism, potency, and safety profile of cannabinoids as single agents and as complementary drugs.”

https://pubmed.ncbi.nlm.nih.gov/33383838/

“Additionally, much evidence from pre-clinical and clinical studies has been gathered over the last decade, suggesting that multiple substances produced by Cannabis plants have a therapeutic potential, including anticancer properties.”

https://www.mdpi.com/1422-0067/22/1/263/htm

 “Derivatives of the plant Cannabis sativa have been used for centuries for both medical and recreational purposes, as well as industrial. The first proof of its medicinal use comes from ancient China, although there is evidence of its earlier utilization in Europe and Asia. In the 19th century, European practitioners started to employ cannabis extracts to treat tetanus, convulsions, and mental diseases and, in 1851, cannabis made its appearance in the Pharmacopoeia of the United States as an analgesic, hypnotic and anticonvulsant. It was only in 1937 that the Marijuana Tax Act prohibited the use of this drug in the USA. The general term Cannabis is commonly used by the scientific and scholar community to indicate derivatives of the plant Cannabis sativa. The word cannabinoid is a term describing chemical compounds that are either derivate of Cannabis (phytocannabinoids) or artificial analogues (synthetic) or are produced endogenously by the body (endocannabinoids). A more casual term “marijuana” or “weed”, a compound derived from dried Cannabis flower tops and leaves, has progressively superseded the term cannabis when referred to its recreational use. The 2018 World health organisation (WHO) data suggest that nearly 2.5% of the global population (147 million) uses marijuana and some countries, such as Canada and Uruguay, have already legalised it. Due to its controversial history, the medicinal use of cannabinoids has always been a centre of debate. The isolation and characterisation of Δ⁹ tetrahydrocannabinol (THC), the major psychoactive component of cannabis and the detection of two human cannabinoid receptor (CBRs) molecules renewed interest in the medical use of cannabinoids, boosting research and commercial heed in this sector. Some cannabinoid-based drugs have been approved as medications, mainly as antiemetic, antianorexic, anti-seizure remedies and in cancer and multiple sclerosis patients’ palliative care. Nevertheless, due to the stigma commonly associated with these compounds, cannabinoids’ potential in the treatment of conditions such as cancer is still largely unknown and therefore underestimated.”

https://pubmed.ncbi.nlm.nih.gov/33422460/

https://www.sciencedirect.com/science/article/abs/pii/S2212492620300853?via%3Dihub

 “Cannabidiol (CBD) is one of the most popular emerging plant extracts that is being investigated for its wide range of potential health benefits.

This experiment tests how B16 mice melanoma cells, are affected by four different concentrations (0.2 mg/mL, 0.04 mg/mL, 0.008 mg/mL and 0.0016 mg/mL) of 99% CBD oil.

The results of this experiment demonstrate that CBD significantly inhibited melanoma cell growth in-vitro at 0.2 mg/mL and 0.04 mg/mL.

This shows that CBD has the potential to inhibit melanoma cell growth in vertebrates, namely mice.”

https://pubmed.ncbi.nlm.nih.gov/33428525/

“Cannabis sativa contains more than 500 constituents, yet the anticancer properties of the vast majority of cannabis compounds remains unknown. We aimed to identify cannabis compounds and their combinations presenting cytotoxicity against bladder urothelial carcinoma (UC), the most common urinary system cancer.

An XTT assay was used to determine cytotoxic activity of C. sativa extracts on T24 and HBT-9 cell lines. Extract chemical content was identified by high-performance liquid chromatography (HPLC). Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and cell cycle, using stained F-actin and nuclei. Scratch and transwell assays were used to determine cell migration and invasion, respectively. Gene expression was determined by quantitative Polymerase chain reaction (PCR).

The most active decarboxylated extract fraction (F7) of high-cannabidiol (CBD) C. sativa was found to contain cannabichromene (CBC) and Δ9-tetrahydrocannabinol (THC). Synergistic interaction was demonstrated between CBC + THC whereas cannabinoid receptor (CB) type 1 and type 2 inverse agonists reduced cytotoxic activity.

Treatments with CBC + THC or CBD led to cell cycle arrest and cell apoptosis. CBC + THC or CBD treatments inhibited cell migration and affected F-actin integrity. Identification of active plant ingredients (API) from cannabis that induce apoptosis and affect cell migration in UC cell lines forms a basis for pre-clinical trials for UC treatment.”

https://pubmed.ncbi.nlm.nih.gov/33477303/

https://www.mdpi.com/1420-3049/26/2/465

 “Considering the advantages of using medicinal herbs as supplementary treatments to sensitize conventional anti-cancer drugs, studying functional mechanisms and regulatory effects of Echinacea purpurea (as a non-cannabinoid plant)

and Cannabis sativa (as a cannabinoid plant) are timely and required.

The potential effects of such herbs on lung cancer cell growth, apoptosis, cell cycle distribution, cellular reactive oxygen species (ROS) level, caspase activity and their cannabinomimetic properties on the CB2 receptor are addressed in the current study.

Results: Echinacea purpurea (EP) root extract induced a considerable decrease in A549 viable cells, showing a time and dose-dependent response. The cell toxicity of EP was accompanied by induction of early apoptosis and cell accumulation at the sub G1 phase of the cell cycle. The elevation of cellular ROS level and caspase 3 activity indicate ROS-induced caspase-dependent apoptosis following the treatment of A549 cells by EP extract. The observed effects of EP extract on A549 growth and death were abrogated following blockage of CB2 using AM630, a specific antagonist of the CB2 receptor. Increasing concentrations of Cannabis sativa (CS) induced A549 cell death in a time-dependent manner, followed by induction of early apoptosis, cell cycle arrest at sub G1 phase, elevation of ROS level, and activation of caspase 3. The CB2 blockage caused attenuation of CS effects on A549 cell death which revealed consistency with the effects of EP extract on A549 cells.

Conclusions: The pro-apoptotic effects of EP and CS extracts on A549 cells and their possible regulatory role of CB2 activity might be attributed to metabolites of both herbs. These effects deserve receiving more attention as alternative anti-cancer agents.”

https://pubmed.ncbi.nlm.nih.gov/33446187/

“Both cannabinoid receptors and naturally occurring cannabinoids, known as phytocannabinoids, have potential therapeutic applications based on their pivotal roles in regulating immunologic responses, alleviating inflammation, tumor cell proliferation, angiogenesis, invasion, and migration. Based on the findings, it can be postulated that EP and CS extracts can inhibit lung cancer cell growth and induce apoptosis and should be considered as an alternative anti-cancer agent in lung cancer.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809807/

“Background: Breast Cancer (BC), a common death-causing disease and the deadliest cancer next to lung cancer, is characterized by an abnormal growth of cells in the tissues of the breast. BC chemotherapy is marked by targeting the activities of some receptors such as Estrogen Receptor alpha (ER-α). At present, one of the most commonly used and approved marketed therapeutic drug for BC is tamoxifen. Despite the short term success of tamoxifen usage, its long time treatment has been associated with significant side effects. Therefore, there is a pressing need for the development of novel anti-estrogens for the prevention and treatment of BC.

Objective: In this study, we evaluate the inhibitory effect of Cannabis Sativa phyto-constituents on ER-α.

Method: Glide and Induced Fit Docking followed by ADME, Automated QSAR and Binding free energy (ΔGbind) studies were used to evaluate the anti-breast cancer and ER-α inhibitory activity of Cannabis sativa, which has been reported to be effective in inhibiting breast cancer cell proliferation.

Results: Phyto-constituents of Cannabis sativa possess lower docking scores and good ΔGbind when compared to that of tamoxifen. ADME and AutoQSAR studies revealed that our lead compounds demonstrated the properties required to make them promising therapeutic agents.

Conclusion: The results of this study suggest that Naringenin, Dihydroresveratrol, Baicalein, Apigenin and Cannabitriol could have relatively better inhibitory activity than tamoxifen and could be a better and patent therapeutic candidate in the treatment of BC. Further research such as in vivo and/or in vitro assays could be conducted to attest the ability of these compounds.”

https://pubmed.ncbi.nlm.nih.gov/33563181/

https://www.eurekaselect.com/190950/article

“Glioblastoma is the most aggressive cancer among primary brain tumours. As with other cancers, the incidence of glioblastoma is increasing; despite modern therapies, the overall mean survival of patients post-diagnosis averages around 16 months, a figure that has not changed in many years. Cannabigerol (CBG) has only recently been reported to prevent the progression of certain carcinomas and has not yet been studied in glioblastoma. Here, we have compared the cytotoxic, apoptotic, and anti-invasive effects of the purified natural cannabinoid CBG together with CBD and THC on established differentiated glioblastoma tumour cells and glioblastoma stem cells. CBG and THC reduced the viability of both types of cells to a similar extent, whereas combining CBD with CBG was more efficient than with THC. CBD and CBG, both alone and in combination, induced caspase-dependent cell apoptosis, and there was no additive THC effect. Of note, CBG inhibited glioblastoma invasion in a similar manner to CBD and the chemotherapeutic temozolomide. We have demonstrated that THC has little added value in combined-cannabinoid glioblastoma treatment, suggesting that this psychotropic cannabinoid should be replaced with CBG in future clinical studies of glioblastoma therapy.”

https://pubmed.ncbi.nlm.nih.gov/33562819/

“Among primary brain tumours, glioblastoma is the most aggressive. As early relapses are unavoidable despite standard-of-care treatment, the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone or in combination have been suggested as a combined treatment strategy for glioblastomas. However, the known psychoactive effects of THC hamper its medical applications in these patients with potential cognitive impairment due to the progression of the disease. Therefore, nontoxic cannabigerol (CBG), being recently shown to exhibit anti-tumour properties in some carcinomas, is assayed here for the first time in glioblastoma with the aim to replace THC. We indeed found CBG to effectively impair the relevant hallmarks of glioblastoma progression, with comparable killing effects to THC and in addition inhibiting the invasion of glioblastoma cells. Moreover, CBG can destroy therapy-resistant glioblastoma stem cells, which are the root of cancer development and extremely resistant to various other treatments of this lethal cancer. CBG should present a new yet unexplored adjuvant treatment strategy of glioblastoma.”

https://www.mdpi.com/2073-4409/10/2/340

“Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic alterations in TP53 and PTEN tumor suppressor genes rendering resistance to standard chemotherapeutics. Cannabinoid type 1 and 2 (CB1/CB2) receptor expression in GBMs and antitumor activity of cannabinoids in glioma cells and animal models, raised promises for a targeted treatment of these tumors. The susceptibility of human glioma cells to CB2-agonists and their mechanism of action are not fully elucidated. We determined CB1 and CB2 expression in 14 low-grade and 21 high-grade tumor biopsies, GBM-derived primary cultures and established cell lines. The non-selective CB receptor agonist WIN55,212-2 (but not its inactive enantiomer) or the CB2-selective agonist JWH133 induced apoptosis in patient-derived glioma cultures and five established glioma cell lines despite p53 and/or PTEN deficiency. Growth inhibitory efficacy of cannabinoids correlated with CB1/CB2 expression (EC₅₀ WIN55,212-2: 7.36-15.70 µM, JWH133: 12.15-143.20 µM). Treatment with WIN55,212-2 or JWH133 led to activation of the apoptotic mitochondrial pathway and DNA fragmentation. Synthetic cannabinoid action was associated with the induction of autophagy and knockdown of autophagy genes augmented cannabinoid-induced apoptotic cell death. The high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, makes cannabinoids promising anti-glioma therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/33499365/

“Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic defects in TP53 and PTEN tumor suppressor genes, which render tumors refractory to standard chemotherapeutics.

Natural and synthetic cannabinoids showed antitumor activity in glioma cells and animal glioma models.

Due to differences in the expression of cannabinoid type 2 receptors (CB2), which are abundant in GBMs but absent from a healthy brain, we tested synthetic cannabinoids for their ability to kill numerous glioma cells. We performed multiple biochemical analyses to determine which cell death pathways are activated in human glioma cells. We demonstrate high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, which makes cannabinoids promising anti-glioma therapeutics.”

https://www.mdpi.com/2072-6694/13/3/419

 “Cannabis was extensively utilized for its medicinal properties till the 19^th 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