Category Archives: Cancer

Anti-cancer properties of cannflavin A and potential synergistic effects with gemcitabine, cisplatin, and cannabinoids in bladder cancer

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“Introduction: Several studies have shown anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of most compounds present in cannabis in bladder cancer and how these compounds could potentially positively or negatively impact the actions of chemotherapeutic agents. Our study aims to evaluate the effects of a compound found in Cannabis sativa that has not been extensively studied to date, cannflavin A, in bladder cancer cell lines. We aimed to identify whether cannflavin A co-treatment with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, is able to produce synergistic effects. We also evaluated whether co-treatment of cannflavin A with various cannabinoids could produce synergistic effects.

Results: Cell viability of bladder cancer cell lines was affected in a concentration-dependent fashion in response to cannflavin A, and its combination with gemcitabine or cisplatin induced differential responses-from antagonistic to additive-and synergism was also observed in some instances, depending on the concentrations and drugs used. Cannflavin A also activated apoptosis via caspase 3 cleavage and was able to reduce invasion by 50%. Interestingly, cannflavin A displayed synergistic properties with other cannabinoids like Δ9-tetrahydrocannabinol, cannabidiol, cannabichromene, and cannabivarin in the bladder cancer cell lines.

Discussion: Our results indicate that compounds from Cannabis sativa other than cannabinoids, like the flavonoid cannflavin A, can be cytotoxic to human bladder transitional carcinoma cells and that this compound can exert synergistic effects when combined with other agents. In vivo studies will be needed to confirm the activity of cannflavin A as a potential agent for bladder cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/35869542/

“A study recently demonstrated that the combination of Δ9-tetrahydrocannabinol and cannabichromene produced synergistic effects in a bladder cancer model, while another focused on the effects of cannabidiol and their potential formulation within nanoparticles to treat bladder cancer. Here, we show that other compounds from cannabis, like cannflavin A, may also induce beneficial cytotoxic and synergistic effects on bladder cancer cells. Our results also showed the ability of cannabinoids, other than Δ9-tetrahydrocannabinol, to produce synergistic effects when combined with the flavonoid cannflavin A.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00151-y


Protective Effects of Cannabis sativa on chemotherapy-induced nausea in a rat: Involvement of CB1 receptors

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“Cyclophosphamide is an anticancer and immunosuppressive agent used in the treatment of various malignancies but causing gastrointestinal distress.

Cannabis sativa (C. sativa) and its derivatives have been used for the treatment of human gastrointestinal disorders. A purpose of this study was to investigate the effect of C. sativa on nausea induced by cyclophosphamide in rats.

Results showed that C. sativa ameliorates cyclophosphamide-induced emesis by increasing in body weight and normal diet intake with a decrease in kaolin diet intake after 7 days. Moreover, C. sativa significantly decreases (serotonin) 5HT, dopamine and noradrenaline, as well as, decreasing oxidative stress and inflammation. Administration of C. sativa significantly increased the expression of CB1R in intestinal homogenate. Treatment with C. sativa, also, improved the histological feature of an intestinal tissue.

These results suggested that C. sativa possess antiemetic, antioxidant and anti-inflammatory effects in chemotherapy-induced nausea in rats by activating CB1R.”

https://pubmed.ncbi.nlm.nih.gov/35861135/

https://onlinelibrary.wiley.com/doi/10.1111/fcp.12821

Investigating the Effects of a Synthetic Cannabinoid on the Pathogenesis of Leukemia and Leukemic Stem Cells: A New Therapeutic Approach

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“The popularity and usage of synthetic cannabinoids (SCs) are increasing due to their easy accessibility and psychoactive effects worldwide. Studies on cannabinoids on leukemic stem cells (LSC) and hematopoietic stem cells (HSCs), which are the precursors of leukemia cells, generally depend on the natural cannabinoid delta-9-THC. As there is only a limited number of studies focusing on the results of SC applications, the reflections upon LSCs have to be clarified.

In this study, biological responses and antileukemic effects of JWH-018-one of the first produced and widely used SCs-were evaluated upon leukemia cells. Whether JWH-018 exhibited a preventive effect on both leukemic and HSCs was evaluated by presenting a therapeutic approach for the first time in the literature. Cells were analyzed in case of cell proliferation, apoptosis, and transcriptional expression profiling of some significant JAK/STAT and AKT/mTOR pathways, apoptotic, cell cycle regulation, and epigenetic chromatin remodeling-related genes following JWH-018 treatment.

In conclusion, however, further studies are still needed upon both HSCs and LSCs to illuminate the effects of SCs on leukemogenesis on chronic myeloid leukemia (CML) more clearly; we consider that the JWH-018 can provide a therapeutic effect on the pathogenesis of leukemia and particularly upon LSCs and SCs might have therapeutic potential in addition to current therapy.”

https://pubmed.ncbi.nlm.nih.gov/35834597/

https://www.liebertpub.com/doi/10.1089/can.2021.0180

“Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns. Our study provides rigorous data to support clinical evaluation of THC as a low-toxic therapy option in a well defined subset of acute leukemia patients.”

https://pubmed.ncbi.nlm.nih.gov/26775260/

“Cannabinoid CP55940 selectively induces apoptosis in Jurkat cells and in ex vivo T-cell acute lymphoblastic leukemia through H 2 O 2 signaling mechanism. Our findings support the use of cannabinoids as a potential treatment for T-ALL cells.”

https://pubmed.ncbi.nlm.nih.gov/32540572/

“CP 55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis)”  https://en.wikipedia.org/wiki/CP_55,940

“Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria. Plant-derived cannabinoids, including Delta9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells”

https://pubmed.ncbi.nlm.nih.gov/16908594/


The Combination of Δ 9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

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“Phytocannabinoids represent a promising approach in glioblastoma therapy.

Previous work has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations of psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly increases cell death.

In the present work, the glioblastoma cell lines U251MG and U138MG were used to investigate whether the combination of THC and CBD in a 1:1 ratio is associated with a disruption of cellular energy metabolism, and whether this is caused by affecting mitochondrial respiration.

Here, the combined administration of THC and CBD (2.5 µM each) led to an inhibition of oxygen consumption rate and energy metabolism. These effects were accompanied by morphological changes to the mitochondria, a release of mitochondrial cytochrome c into the cytosol and a marked reduction in subunits of electron transport chain complexes I (NDUFA9, NDUFB8) and IV (COX2, COX4). Experiments with receptor antagonists and inhibitors showed that the degradation of NDUFA9 occurred independently of the activation of the cannabinoid receptors CB1, CB2 and TRPV1 and of usual degradation processes mediated via autophagy or the proteasomal system.

In summary, the results describe a previously unknown mitochondria-targeting mechanism behind the toxic effect of THC and CBD on glioblastoma cells that should be considered in future cancer therapy, especially in combination strategies with other chemotherapeutics.”

https://pubmed.ncbi.nlm.nih.gov/35804909/

“Cannabidiol (CBD) is a phytocannabinoid from Cannabis sativa L. that exhibits no psychoactivity and, like the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC), shows anticancer effects in preclinical cell and animal models. Previous studies have indicated a stronger cancer-targeting effect when THC and CBD are combined. Here, we investigated how the combination of THC and CBD in a 1:1 ratio affects glioblastoma cell survival. The compounds were found to synergistically enhance cell death, which was attributed to mitochondrial damage and disruption of energy metabolism. A detailed look at the mitochondrial electron transfer chain showed that THC/CBD selectively decreased certain subunits of complexes I and IV. These data highlight the fundamental changes in cellular energy metabolism when cancer cells are exposed to a mixture of cannabinoids and underscore the potential of combining cannabinoids in cancer treatment.”

https://www.mdpi.com/2072-6694/14/13/3129


Therapeutic Potential of Cannabinoids on Tumor Microenvironment: A Molecular Switch in Neoplasia Transformation

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“The efficacy of chemotherapy depends on the tumor microenvironment. This microenvironment consists of a complex cellular network that can exert both stimulatory and inhibitory effects on tumor genesis.

Given the increasing interest in the effectiveness of cannabis, cannabinoids have gained much attention as a potential chemotherapy drug. Cannabinoids are a group of marker compounds found in Cannabis sativa L., more commonly known as marijuana, a psychoactive drug used since ancient times for pain management.

Although the anticancer potential of C. sativa, has been recognized previously, increased attention was generated after discovering the endocannabinoid system and the successful production of cannabinoid receptors.

In vitro and in vivo studies on various tumor models have shown therapeutic efficiency by modifying the tumor microenvironment.

This review summarizes the key literature surrounding the role of cannabinoids in the tumor microenvironment and their future promise in cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/35796303/

“Cannabis sativa L. is a natural source of valuable compounds that comprise cannabinoid agonists and antagonists, which have recently been scanned for future applications as anti-tumor drugs. Cannabinoids have mostly been used as a part of palliative care to alleviate pain, relieve nausea, and stimulate appetite in cancer patients. Although not yet approved for treating tumor progression, cannabinoid agonist/antagonists on the tumor microenvironment have been studied for the last 43 years. Research on cannabinoids and their potential therapeutic function has been ongoing since 1971. Numerous in vitro and in vivo studies have demonstrated the anti-cancer effects of cannabinoids in various cancer types.”

https://journals.sagepub.com/doi/10.1177/15347354221096766


Cannabis: Chemistry, extraction and therapeutic applications

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Chemosphere

“Cannabis, a genus of perennial indigenous plants is well known for its recreational and medicinal activities. Cannabis and its derivatives have potential therapeutic activities to treat epilepsy, anxiety, depression, tumors, cancer, Alzheimer’s disease, Parkinson’s disease, to name a few.

This article reviews some recent literature on the bioactive constituents of Cannabis, commonly known as phytocannabinoids, their interactions with the different cannabinoids and non-cannabinoid receptors as well as the significances of these interactions in treating various diseases and syndromes.

The biochemistry of some notable cannabinoids such as tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene and their carboxylic acid derivatives is explained in the context of therapeutic activities.

The medicinal features of Cannabis-derived terpenes are elucidated for treating several neuro and non-neuro disorders. Different extraction techniques to recover cannabinoids are systematically discussed. Besides the medicinal activities, the traditional and recreational utilities of Cannabis and its derivatives are presented. A brief note on the legalization of Cannabis-derived products is provided.

This review provides comprehensive knowledge about the medicinal properties, recreational usage, extraction techniques, legalization and some prospects of cannabinoids and terpenes extracted from Cannabis.”

https://pubmed.ncbi.nlm.nih.gov/34838836/

“Cannabinoids have therapeutic effects against various health disorders.•

Medicinal effects are due to the interactions of cannabinoids with bio-receptors.•

Cannabinoids can be extracted from Cannabis plant products by eco-friendly extraction methods.”

https://www.sciencedirect.com/science/article/abs/pii/S0045653521034846?via%3Dihub

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Receptor-targeted nanoparticles modulate cannabinoid anticancer activity through delayed cell internalization

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Scientific Reports

“Δ9-tetrahydrocannabinol (Δ9-THC) is known for its antitumor activity and palliative effects.

However, its unfavorable physicochemical and biopharmaceutical properties, including low bioavailability, psychotropic side effects and resistance mechanisms associated to dosing make mandatory the development of successful drug delivery systems.

In this work, transferring (Tf) surface-modified Δ9-THC-loaded poly(lactide-co-glycolic) nanoparticles (Tf-THC-PLGA NPs) were proposed and evaluated as novel THC-based anticancer therapy. Furthermore, in order to assess the interaction of both the nanocarrier and the loaded drug with cancer cells, a double-fluorescent strategy was applied, including the chemical conjugation of a dye to the nanoparticle polymer along with the encapsulation of either a lipophilic or a hydrophilic dye.

Tf-THC PLGA NPs exerted a cell viability decreased down to 17% vs. 88% of plain nanoparticles, while their internalization was significantly slower than plain nanoparticles. Uptake studies in the presence of inhibitors indicated that the nanoparticles were internalized through cholesterol-associated and clathrin-mediated mechanisms.

Overall, Tf-modification of PLGA NPs showed to be a highly promising approach for Δ9-THC-based antitumor therapies, potentially maximizing the amount of drug released in a sustained manner at the surface of cells bearing cannabinoid receptors.”

https://pubmed.ncbi.nlm.nih.gov/35079042/

“The potential therapeutic applications of marijuana, firstly reported in 1997 by the National Institutes of Health (NIH, USA), are attributed to a great extent to its main component, Δ9-tetrahydrocannabinol (Δ9-THC)1. This cannabinoid continues to attract special attention in oncology due to its palliative effects and antitumor activity; Δ9-THC has been reported to inhibit tumor angiogenesis and cell growth in malignant tissues, leading to cell death.”

“Δ9-THC has been reported to inhibit tumor angiogenesis and cell growth in malignant tissues.”

“Overall, Tf-modification of PLGA NPs seemed a highly promising approach for Δ9-THC-based antitumor therapies, aiming at a prolonged action of the carrier at the target cell surface. Moreover, the translation of this strategy to the delivery of alternative active pharmaceutical ingredients with pharmacological targets on the surface of cells could lead to advances in related therapies.”

https://www.nature.com/articles/s41598-022-05301-z

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer

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“There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT).

Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer.

In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients.

We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them.

We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects.

In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.”

https://pubmed.ncbi.nlm.nih.gov/35743206/

https://www.mdpi.com/1422-0067/23/12/6766


Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines-An Isobolographic Analysis

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“The medical application of cannabidiol (CBD) has been gathering increasing attention in recent years. This non-psychotropic cannabis-derived compound possesses antiepileptic, antipsychotic, anti-inflammatory and anxiolytic properties. Recent studies report that it also exerts antineoplastic effects in multiple types of cancers, including melanoma.

In this in vitro study we tried to reveal the anticancer properties of CBD in malignant melanoma cell lines (SK-MEL 28, A375, FM55P and FM55M2) administered alone, as well as in combination with mitoxantrone (MTX) or cisplatin (CDDP).

The effects of CBD on the viability of melanoma cells were measured by the MTT assay; cytotoxicity was determined in the LDH test and proliferation in the BrdU test. Moreover, the safety of CBD was tested in human keratinocytes (HaCaT) in LDH and MTT tests.

Results indicate that CBD reduces the viability and proliferation of melanoma-malignant cells and exerts additive interactions with MTX. Unfortunately, CBD produced antagonistic interaction when combined with CDDP. CBD does not cause significant cytotoxicity in HaCaT cell line.

In conclusion, CBD may be considered as a part of melanoma multi-drug therapy when combined with MTX. A special attention should be paid to the combination of CBD with CDDP due to the antagonistic interaction observed in the studied malignant melanoma cell lines.”

https://pubmed.ncbi.nlm.nih.gov/35743195/

https://www.mdpi.com/1422-0067/23/12/6752

Mechanisms of Cannabidiol (CBD) in Cancer Treatment: A Review

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“Cannabis sativa L. (Cannabis) and its bioactive compounds, including cannabinoids and non-cannabinoids, have been extensively studied for their biological effects in recent decades. Cannabidiol (CBD), a major non-intoxicating cannabinoid in Cannabis, has emerged as a promising intervention for cancer research.

The purpose of this review is to provide insights into the relationship between CBD and cancer based on recent research findings.

The anticancer effects of CBD are mainly mediated via its interaction with the endocannabinoid system, resulting in the alleviation of pain and the promotion of immune regulation. Published reviews have focused on the applications of CBD in cancer pain management and the possible toxicological effects of its excessive consumption.

In this review, we aim to summarize the mechanisms of action underlying the anticancer activities of CBD against several common cancers. Studies on the efficacy and mechanisms of CBD on cancer prevention and intervention in experimental models (i.e., cell culture- and animal-based assays) and human clinical studies are included in this review.”

https://pubmed.ncbi.nlm.nih.gov/35741337/

“Emerging evidence suggests positive outcomes from the use of CBD as a cancer treatment. CBD can relieve cancer pain and ease the side effects of chemotherapy; however, there is less research about the mechanism of CBD’s anticancer effects. In this article, recent studies on the efficacy and mechanisms of CBD’s anticancer effects in cell- and animal-based models and human clinical studies are reviewed.”

https://www.mdpi.com/2079-7737/11/6/817