Special Issue "Cannabinoids and Cancer"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 November 2020).

Special Issue Editors

Prof. Dr. Marco Falasca
Website
Guest Editor
Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences | Faculty of Health Sciences. Curtin University, Perth, Australia
Interests: signal transduction; cancer invasion and metastasis; pancreatic cancer; phosphoinositide signalling; cannabinoids; cannabinoid receptors
Special Issues and Collections in MDPI journals
Prof. Dr. Mauro Maccarrone
Website
Guest Editor
1. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
2. European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy
Interests: arachidonate cascade; bioactive lipids; biomarkers; cell membranes; endocannabinoids; resolvins; signal transduction
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues, 

The endocannabinoid system (ECS) is a complex array of endogenous cannabinoid ligands, cannabinoid receptors (CBR), metabolic enzymes and transporters that are responsible for the biosynthesis and degradation of endocannabinoids. ECS regulates homeostasis within the organism and controls housekeeping processes, such as regulation of appetite, energy metabolism and immune functions. There are three main categories of cannabinoids: endogenous cannabinoids, synthetic cannabinoids and phytocannabinoids. Endogenous cannabinoids are those produced in the human body or in animals and include anandamide or arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Phytocannabinoids are cannabinoids derived from extracts of the plant Cannabis sativa or indica L. There are more than 100 different phytocannabinoids, of which the most common and bioactive are THC (Δ9-tetrahydrocannabinol), CBD (cannabidiol), and CBN (cannabinol). Many studies have reported that the ECS could be a new interesting target for the treatment of many cancer types. The potential of modulating the ECS has attracted interest in cancer research and has been extensively studied, particularly for its anticancer, anti-proliferative, anti-angiogenic, proapoptotic, and anti-metastatic activity. Several types of cancer have been shown to be suppressed by cannabinoids such as breast, glioblastoma, pancreatic, and prostate cancer. In addition, emerging evidence suggests that cannabinoids may improve the efficacy of available therapeutic options for cancer treatments such as chemotherapy, immunotherapy, radiation, surgery, and the use of targeted therapy. This Special Issue intends to publish original research, expert opinions, and reviews to add to the growing knowledge on cannabinoids and cancer. Short reports and methodological papers will also be considered.

Prof. Dr. Marco Falasca
Prof. Dr. Mauro Maccarrone
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer treatment
  • cannabinoids
  • cannabinoid receptors
  • cannabidiol
  • tetrahydrocannbinol

Published Papers (8 papers)

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Research

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Open AccessArticle
THC Reduces Ki67-Immunoreactive Cells Derived from Human Primary Glioblastoma in a GPR55-Dependent Manner
Cancers 2021, 13(5), 1064; https://doi.org/10.3390/cancers13051064 - 03 Mar 2021
Viewed by 163
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Open AccessArticle
Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in TP53 or PTEN Tumor Suppressors
Cancers 2021, 13(3), 419; https://doi.org/10.3390/cancers13030419 - 22 Jan 2021
Viewed by 416
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Open AccessArticle
Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma
Cancers 2021, 13(2), 330; https://doi.org/10.3390/cancers13020330 - 18 Jan 2021
Viewed by 685
Abstract
Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their [...] Read more.
Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their use in pediatric brain cancers is lacking. Here we investigated the potential role for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in medulloblastoma and ependymoma. Dose-dependent cytotoxicity of medulloblastoma and ependymoma cells was induced by THC and CBD in vitro, and a synergistic reduction in viability was observed when both drugs were combined. Mechanistically, cannabinoids induced cell cycle arrest, in part by the production of reactive oxygen species, autophagy, and apoptosis; however, this did not translate to increased survival in orthotopic transplant models despite being well tolerated. We also tested the combination of cannabinoids with the medulloblastoma drug cyclophosphamide, and despite some in vitro synergism, no survival advantage was observed in vivo. Consequently, clinical benefit from the use of cannabinoids in the treatment of high-grade medulloblastoma and ependymoma is expected to be limited. This study emphasizes the importance of preclinical models in validating therapeutic agent efficacy prior to clinical trials, ensuring that enrolled patients are afforded the most promising therapies available. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Open AccessArticle
Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome
Cancers 2020, 12(9), 2447; https://doi.org/10.3390/cancers12092447 - 28 Aug 2020
Cited by 3 | Viewed by 2077
Abstract
Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including [...] Read more.
Cannabis or its derivatives are widely used by patients with cancer to help with cancer symptoms and treatment side effects. However, cannabis has potent immunomodulatory properties. To determine if cannabis consumption during immunotherapy affects therapy outcomes, we conducted a prospective observatory study including 102 (68 immunotherapy and 34 immunotherapy plus cannabis) consecutive patients with advanced cancers who initiated immunotherapy. Cannabis consumption correlated with a significant decrease in time to tumor progression and overall survival. On the other hand, the use of cannabis reduced therapy-related immune-related adverse events. We also tested the possibility that cannabis may affect the immune system or the tumor microenvironment through the alteration of the endocannabinoid system. We analyzed a panel of serum endocannabinoids (eCBs) and eCB-like lipids, measuring their levels before and after immunotherapy in both groups. Levels of serum eCBs and eCB-like lipids, before immunotherapy, showed no significant differences between cannabis users to nonusers. Nevertheless, the levels of four eCB and eCB-like compounds were associated with patients’ overall survival time. Collectively, cannabis consumption has considerable immunomodulatory effects, and its use among cancer patients needs to be carefully considered due to its potential effects on the immune system, especially during treatment with immunotherapy. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Review

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Open AccessReview
The Role of Cannabinoids as Anticancer Agents in Pediatric Oncology
Cancers 2021, 13(1), 157; https://doi.org/10.3390/cancers13010157 - 05 Jan 2021
Viewed by 1022
Abstract
Cannabinoids are a group of chemicals that bind to receptors in the human body and, in turn, modulate the endocannabinoid system (ECS). They can be endogenously produced, synthetic, or derived from the plant Cannabis sativa L. Research over the past several decades [...] Read more.
Cannabinoids are a group of chemicals that bind to receptors in the human body and, in turn, modulate the endocannabinoid system (ECS). They can be endogenously produced, synthetic, or derived from the plant Cannabis sativa L. Research over the past several decades has shown that the ECS is a cellular communication network essential to maintain multiple biological functions and the homeostasis of the body. Indeed, cannabinoids have been shown to influence a wide variety of biological effects, including memory, pain, reproduction, bone remodeling or immunity, to name a few. Unsurprisingly, given these broad physiological effects, alterations of the ECS have been found in different diseases, including cancer. In recent years, the medical use of cannabis has been approved in different countries for a variety of human conditions. However, the use of these compounds, specifically as anticancer agents, remains controversial. Studies have shown that cannabinoids do have anticancer activity in different tumor types such as breast cancer, melanoma, lymphoma and adult brain cancer. Specifically, phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been shown to induce apoptosis and inhibit proliferation of adult cancer cells, as well as modulate angiogenesis and metastasis. Despite increasing evidence that cannabinoids elicit antitumor effects in adult cancers, there is minimal data available on their effects in children or in pediatric cancers despite public and clinical demand for information. Here we describe a comprehensive and critical review of what is known about the effects of cannabinoids on pediatric cancers, highlight current gaps in knowledge and identify the critical issues that need addressing before considering these promising but controversial drugs for use in pediatric oncology. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Open AccessReview
(Endo)Cannabinoids and Gynaecological Cancers
Cancers 2021, 13(1), 37; https://doi.org/10.3390/cancers13010037 - 25 Dec 2020
Viewed by 843
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Open AccessReview
The Interplay between Cancer Biology and the Endocannabinoid System—Significance for Cancer Risk, Prognosis and Response to Treatment
Cancers 2020, 12(11), 3275; https://doi.org/10.3390/cancers12113275 - 05 Nov 2020
Cited by 2 | Viewed by 692
Abstract
The various components of the endocannabinoid system (ECS), such as the cannabinoid receptors (CBRs), cannabinoid ligands, and the signalling network behind it, are implicated in several tumour-related states, both as favourable and unfavourable factors. This review analyses the ECS’s complex involvement in the [...] Read more.
The various components of the endocannabinoid system (ECS), such as the cannabinoid receptors (CBRs), cannabinoid ligands, and the signalling network behind it, are implicated in several tumour-related states, both as favourable and unfavourable factors. This review analyses the ECS’s complex involvement in the susceptibility to cancer, prognosis, and response to treatment, focusing on its relationship with cancer biology in selected solid cancers (breast, gastrointestinal, gynaecological, prostate cancer, thoracic, thyroid, CNS tumours, and melanoma). Changes in the expression and activation of CBRs, as well as their ability to form distinct functional heteromers affect the cell’s tumourigenic potential and their signalling properties, leading to pharmacologically different outcomes. Thus, the same ECS component can exert both protective and pathogenic effects in different tumour subtypes, which are often pathologically driven by different biological factors. The use of endogenous and exogenous cannabinoids as anti-cancer agents, and the range of effects they might induce (cell death, regulation of angiogenesis, and invasion or anticancer immunity), depend in great deal on the tumour type and the specific ECS component that they target. Although an attractive target, the use of ECS components in anti-cancer treatment is still interlinked with many legal and ethical issues that need to be considered. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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Open AccessReview
Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer
Cancers 2020, 12(4), 1033; https://doi.org/10.3390/cancers12041033 - 23 Apr 2020
Cited by 8 | Viewed by 4168
Abstract
Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited [...] Read more.
Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆9-tetrahydrocannabinol (∆9-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆9-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids. Full article
(This article belongs to the Special Issue Cannabinoids and Cancer)
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