Category Archives: Cancer

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics

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“The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer’s Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.”

https://pubmed.ncbi.nlm.nih.gov/37943817/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0293666

The potential of cannabinoids in the treatment of lung cancer

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Publikacje pracowników AWF - kwiecień 2023 - Akademia Wychowania Fizycznego we Wrocławiu

“Introduction: Lung cancer is the number-one cause of death due to neoplasms worldwide. The 5-year overall survival rate is only 22%. In advanced stages, the therapeutic options are limited to chemotherapy, radiotherapy, molecularly targeted therapy and immunotherapy. Phytocannabinoids, the components of Cannabis sativa, their synthetic derivatives and endogenous cannabinoids have demonstrated anticancer activity in various common cancers – breast, prostate, colorectal and lung cancers, among others. The aim of this review was to assess the potential value of cannabinoids in the treatment of lung cancer.

State of knowledge: The majority of preclinical studies demonstrates that cannabinoids inhibit lung cancer cell viability both in vitro and in vivo. The main mechanism of anticancer  activity is the induction of apoptosis, triggered by activation of CB1, CB2 and TRPV1 receptors or independently via other pathways. Cannabinoids influence the components of the tumour microenvironment – cancer associated fibroblasts, macrophages and lymphokine-activated-killer cells. Cannabinoids alter leukocyte infiltration into anti-cancer proportions, inhibit expression of EGFR and PAI-1 and increase the expression of TIMP-1. As a result they induce cytotoxicity, decrease proliferation, migration and invasive potential of lung cancer cells, suppress angiogenesis and metastasis forming. Patients with advanced lung cancer may also benefit from analgesic, antiemetic and appetite improving properties of cannabinoids.

Summary: Cannabinoids can be a supplementary agent in systemic anticancer therapeutic regimen in the future. The exact mechanisms of action, specific doses in anticancer treatment, routes of administration and interactions with other anticancer drugs has yet to be determined. Thus the clinical studies on cannabinoids in lung cancer should be performed in the future.”

https://apcz.umk.pl/JEHS/article/view/39529

Involvement of cannabinoid receptors and adenosine A2B receptor in enhanced migration of lung cancer A549 cells induced by γ-ray irradiation

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“Residual cancer cells after radiation therapy may acquire malignant phenotypes such as enhanced motility and migration ability, and therefore it is important to identify targets for preventing radiation-induced malignancy in order to increase the effectiveness of radiotherapy. G-Protein-coupled receptors (GPCRs) such as adenosine A2B receptor and cannabinoid receptors (CB1, CB2 and GPR55) may be involved, as they are known to have roles in proliferation, invasion, migration and tumor growth. In this study, we investigated the involvement of A2B and cannabinoid receptors in γ-radiation-induced enhancement of cell migration and actin remodeling, as well as the involvement of cannabinoid receptors in cell migration enhancement via activation of A2B receptor in human lung cancer A549 cells. Antagonists or knockdown of A2B, CB1, CB2 or GPR55 receptor suppressed γ-radiation-induced cell migration and actin remodeling. Furthermore, BAY60-6583 (an A2B receptor-specific agonist) enhanced cell migration and actin remodeling in A549 cells, and this enhancement was suppressed by antagonists or knockdown of CB2 or GPR55, though not CB1 receptor. Our results indicate that A2B receptors and cannabinoid CB1, CB2 and GPR55 receptors all contribute to γ-radiation-induced acquisition of malignant phenotypes, and in particular that interactions of A2B receptor and cannabinoid CB2 and GPR55 receptors play a role in promoting cell migration and actin remodeling. A2B receptor-cannabinoid receptor pathways may be promising targets for blocking the appearance of malignant phenotypes during radiotherapy of lung cancer.”

https://pubmed.ncbi.nlm.nih.gov/37926527/

https://www.jstage.jst.go.jp/article/bpb/advpub/0/advpub_b23-00631/_article

The ameliorative effects of cannabidiol on methotrexate-induced neuroinflammation and neuronal apoptosis via inhibiting endoplasmic reticulum and mitochondrial stress

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“Methotrexate (MTX) is an antineoplastic agent and has neurotoxic effects. It exerts its toxic effect on the brain by triggering inflammation and apoptosis. Cannabidiol (CBD) is an agent known for its antioxidant, anti-inflammatory effects in various tissues. The aim of this study is to examine the protective effects of CBD treatment in various brain structures from MTX damage and to evaluate the effect of intracellular pathways involved in apoptosis. Thirty-two adult Wistar Albino female rats were divided into four groups as control, MTX (20 mg/kg intraperitoneally [i.p.]), MTX + CBD (0.1 mL of 5 mg/kg i.p.), and CBD (for 7 days, i.p.). At the end of the experiment, brain tissues collected for biochemical analyses as total oxidant status (TOS), total antioxidant status, oxidative stress index (OSI), histopathological and immunohistochemical analyses as tumor necrosis factor-α (TNF-α), serotonin, mammalian target of rapamycin (mTOR) staining, genetic analyses as caspase-9 (Cas-9), caspase-12 (Cas-12), C/EBP homologous protein (CHOP), and cytochrome-c (Cyt-c) gene expressions. In the histopathological and immunohistochemical evaluation, hyperemia, microhemorrhage, neuronal loss, and significant decreasing expressions of seratonin were observed in the cortex, hippocampus, and cerebellum regions in the MTX group. mTOR, TNF-α, Cas-9, Cas-12, CHOP, and Cyt-c expressions with TOS and OSI levels were increased in the cortex. It was observed that these findings were reversed after CBD application in all regions. MTX triggers neuronal apoptosis via endoplasmic reticulum and mitochondrial stress while destroying serotonergic neurons. The reversal of the pathological changes with CBD treatment proves that it has anti-inflammatory and antiapoptotic activity in brain.”

https://pubmed.ncbi.nlm.nih.gov/37927177/

https://onlinelibrary.wiley.com/doi/10.1002/jbt.23571

Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment

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“Melanoma is one of the leading fatal forms of cancer, yet from a treatment perspective, we have minimal control over its reoccurrence and resistance to current pharmacotherapies. The endocannabinoid system (ECS) has recently been accepted as a multifaceted homeostatic regulator, influencing various physiological processes across different biological compartments, including the skin. This review presents an overview of the pathophysiology of melanoma, current pharmacotherapy used for treatment, and the challenges associated with the different pharmacological approaches. Furthermore, it highlights the utility of cannabinoids as an additive remedy for melanoma by restoring the balance between downregulated immunomodulatory pathways and elevated inflammatory cytokines during chronic skin conditions as one of the suggested critical approaches in treating this immunogenic tumor.”

https://pubmed.ncbi.nlm.nih.gov/37920964/

“Cannabinoids, including endocannabinoids, phytocannabinoids, and synthetic agents, exert pharmacological effects on the skin by activating the specific cannabinoid receptors CB1 and CB2. Uniquely, the ECS system has been shown in vivo and in vitro to regulate the immune system through its immunomodulatory properties. They can attenuate chronic inflammatory disorders and subsequently enhance anti-tumor characteristics. In addition to their immunomodulatory effects, cannabinoids further mediate multiple anti-cancer pathways, including autophagy, apoptosis, angiogenesis, cell motility, and cell adhesion; moreover, they regulate key inflammatory processes critical to the homeostatic regulation of the tumor microenvironment. “

https://wires.onlinelibrary.wiley.com/doi/10.1002/wsbm.1633

In Vitro Antiproliferative Effect of Cannabis Extract PHEC-66 on Melanoma Cell Lines

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“Melanoma, an aggressive form of skin cancer, can be fatal if not diagnosed and treated early. Melanoma is widely recognized to resist advanced cancer treatments, including immune checkpoint inhibitors, kinase inhibitors, and chemotherapy. Numerous studies have shown that various Cannabis sativa extracts exhibit potential anticancer effects against different types of tumours both in vitro and in vivo. This study is the first to report that PHEC-66, a Cannabis sativa extract, displays antiproliferative effects against MM418-C1, MM329 and MM96L melanoma cells. Although these findings suggest that PHEC-66 has promising potential as a pharmacotherapeutic agent for melanoma treatment, further research is necessary to evaluate its safety, efficacy, and clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/37887294/

“In conclusion, the results of this study demonstrate that PHEC-66 extract derived from Cannabis sativa exerts a significant cytotoxic effect on MM418-C1, MM329, and MM96L melanoma cell lines while having a lesser effect on human keratinocytes (HaCaT), human epidermal melanocytes (HEM), and normal human dermal fibroblasts (NHDF). Although the mechanism of PHEC-66’s anti-melanoma activity remains unknown, this study suggests it may induce apoptotic and necrotic cell death pathways. Further research is necessary to fully comprehend the underlying mechanisms of PHEC-66’s actions and assess its potential as a natural source of anticancer compounds.”

https://www.mdpi.com/2073-4409/12/20/2450

Eight Weeks of Daily Cannabidiol Supplementation Improves Sleep Quality and Immune Cell Cytotoxicity

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“Background: The endocannabinoid system is active in nervous and immune cells and involves the expression of two cannabinoid receptor genes (CB1 and CB2), along with endogenous endocannabinoid ligands, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide), and their synthetic enzymes. Cannabidiol (CBD) is a non-intoxicating exogenous cannabinoid agonist derived from plants that, at high doses, has received FDA approval as an anticonvulsant for epileptic seizures, and at low doses is marketed as a food-grade supplement for improved mental health, sleep quality, and immunological function. At present, the predominance of published CBD clinical research has focused on ameliorative or disease-specific intervention, with few trials investigating CBD effects in healthy populations.

Methods: This clinical study aimed to investigate the effects of 8 weeks of 50 mg oral CBD on mental health, sleep quantity and quality, and immune cell function in healthy, college-aged individuals. Twenty-eight participants (average age 25.9 ± 6.1 y) were randomized to receive either daily oral capsules of 50 mg of CBD (CB, n = 14) or a calorie-matched placebo (CN, n = 14). Participants completed pre- and post-intervention assessments, including anthropometric measurements, mental health surveys, sleep analysis, and immunological function assessments.

Results: After completing the 8-week intervention, there were no significant changes in body weight and BMI (CN: 1.09 ± 0.89%: CB: 1.41 ± 1.07%), or body fat percentage (CN: 9.01 ± 7.51%: CB: 8.57 ± 7.81%), respectively (values are % change pre to post, p > 0.05). There were also no significant differences between CB and CN groups with respect to mental health measures, sleep quantity, or circulating immunophenotype as a result of the intervention. However, the CB group experienced significant improvements in sleep quality measured objectively using a sleep questionnaire (p = 0.0023) and enhanced Natural Killer (NK) immune cell function assessed in situ (p = 0.0125).

Conclusions: Eight weeks of daily 50 mg CBD may improve sleep quality, and NK immunosurveillance in healthy, younger adults.”

https://pubmed.ncbi.nlm.nih.gov/37836465/

“These results collectively support the notion that low dose CBD supplementation may offer benefits in enhancing sleep quality in humans and improving immunosurveillance against cancer cells in situ.”

https://www.mdpi.com/2072-6643/15/19/4173

The potential protective and therapeutic effects of cannabidiol oil on experimental Leukemia induced by DMBA in male rats

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“Background: 7,12-Dimethylbenzanthracene (DMBA) is a member of the polycyclic aromatic hydrocarbon family. It is a member of the polycyclic aromatic hydrocarbon family. It is a mutagenic, carcinogenic, and immunosuppressor agent. Cannabidiol (CBD) is a phytocannabinoid. It has anticonvulsant, anti-inflammatory, anti-anxiety, antioxidant, and anti-cancer properties. The purpose of this study was to investigate the possible protective and therapeutic benefits of CBD oil in DMBA-induced leukemia in rats.

Method: Experimental animals were divided into six groups of five rats each. Group 1 (normal control) included healthy rats. Group 2 included normal rats that received olive oil. Group 3 included normal rats that received CBD. Group 4 included the DMBA-induced leukemic group. Group 5 (prophylactic group) included rats that received CBD as a prophylaxis before IV injection with DMBA. Group 6 (treated group) included DMBA-induced leukemic rats that received CBD as treatment. Liver functions (total, direct and indirect bilirubin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), albumin, globulin, and albumin globulin ratio) were measured. Superoxide dismutase (SOD) and catalase (CAT) were also measured. Total RNA extraction followed by-real time qRT-PCR gene expression of LC3-II, Beclin, mTOR, and P62 was performed. Histopathological examination of liver and spleen tissues was performed.

Results: Administration of CBD in groups 5 and 6 resulted in a significant improvement of the levels of liver functions compared to the leukemic untreated rats. Also, the levels of catalase and SOD significantly increased after treatment with CBD compared to the leukemic group. After treatment with CBD in groups 5 and 6, there were downregulations in the expression of all studied genes compared to leukemic untreated rats. Treatment with CBD was more statistically effective than prophylactic use.

Conclusion: Administration of CBD resulted in a significant improvement in the biochemical, antioxidant status, morphological, and molecular measures in DMBA-induced leukemia in adult male rats. The therapeutic use was more effective than the prophylactic one.”

https://pubmed.ncbi.nlm.nih.gov/37837474/

https://link.springer.com/article/10.1007/s00210-023-02737-6

Cell death induction and intracellular vesicle formation in human colorectal cancer cells treated with Δ9-Tetrahydrocannabinol

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“Background: Δ9-Tetrahydrocannabinol (Δ9-THC) is a principal psychoactive extract of Cannabis sativa and has been traditionally used as palliative medicine for neuropathic pain. Cannabidiol (CBD), an extract of hemp species, has recently attracted increased attention as a cancer treatment, but Δ9-THC is also requiring explored pharmacological application.

Objective: This study evaluated the pharmacological effects of Δ9-THC in two human colorectal cancer cell lines. We investigated whether Δ9-THC treatment induces cell death in human colorectal cancer cells.

Methods: We performed an MTT assay to determine the pharmacological concentration of Δ9-THC. Annxein V and Western blot analysis confirmed that Δ9-THC induced apoptosis in colorectal cancer cells. Metabolic activity was evaluated using MitoTracker staining and ATP determination. We investigated vesicle formation by Δ9-THC treatment using GW9662, known as a PPARγ inhibitor.

Results: The MTT assay showed that treatment with 40 μM Δ9-THC and above inhibited the proliferation of colorectal cancer cells. Multiple intracytoplasmic vesicles were detected upon microscopic observation, and fluorescence-activated cell sorting analysis showed cell death via G1 arrest. Δ9-THC treatment increased the expression of cell death marker proteins, including p53, cleaved PARP-1, RIP1, and RIP3, suggesting that Δ9-THC induced the death of colorectal cancer cells. Δ9-THC treatment also reduced ATP production via changes in Bax and Bcl-2. Δ9-THC regulated intracytoplasmic vesicle formation by modulating the expression of PPARγ and clathrin, adding that antiproliferative activity of Δ9-THC was also affected.

Conclusion: In conclusion, Δ9-THC regulated two functional mechanisms, intracellular vesicle formation and cell death. These findings can help to determine how cannabinoids can be used most effectively to improve the efficacy of cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/37837516/

https://link.springer.com/article/10.1007/s13258-023-01466-7

Reversion of chemoresistance by endocannabinoid-induced ER stress and autophagy activation in ovarian cancer

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“The difficulty of detection at an early stage and the ease of developing resistance to chemotherapy render ovarian cancer (OVC) difficult to cure. Although several novel cancer therapies have been developed recently, drug resistance remains a concern since chemotherapy remains as the most commonly used treatment for cancer patients. Therefore, there is an urgent need to reclaim potential combination treatments for OVC.

So far, there have been several research targeting the endocannabinoid system (ECS) in cancer. Among the various cannabinoid-based drugs, endocannabinoids, which are lipid molecules generated in the body, have been reported to produce many anti-tumor effects; however, research investigating the anti-chemoresistance effect of endocannabinoids in OVC remains unclear.

In this study, we aimed to combine endocannabinoids, anandamide (AEA), and 2-arachidonoylglycerol (2-AG) with chemotherapeutic drugs as a combination approach to treat OVC.

Our results showed that OVC cells expressed both cannabinoid receptors (CBR), CB1 and CB2, suggesting the possibility of endocannabinoid system (ECS) as a target. We found that the anti-chemoresistance effect mediated by endocannabinoids was caused by upregulation of ceramide levels, leading to severe endoplasmic reticulum (ER) stress and increased autophagy in chemoresistant cancer cells. Therefore, chemoresistant cancer cell growth was inhibited, and cell apoptosis was induced under combined treatments. Based on our results, endocannabinoids overcomed chemoresistance of OVC cells in vitro.

Our findings suggest that drugs targeting ECS may have the potential to be adjuvants for chemotherapy by increasing the efficacy of chemotherapeutic drugs and decreasing their side effects.”

https://pubmed.ncbi.nlm.nih.gov/37818056/