Category Archives: Cancer

Canonical DDR activation by EMT inducing agent 5-Fluorouracil is modulated by a cannabinoid based combinatorial approach via inducing autophagy and suppression of vimentin expression

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“Anastasis cascade including induction of Epithelial to Mesenchymal Transition (EMT), DNA repair, and stimulation of pro-survival mediators collectively exaggerate therapy resistance in cancer prognosis. The extensive implications of DNA-damaging agents are clinically proven futile for the rapid development of disease recurrence during treatment regime.

Herein we report a glycosidic derivative of Δ9-tetrahydrocannabinol (THC-9-OG) abrogates sub-toxic doses of 5-Fluorouracil (5FU) induced EMT in colon cancer cells nullifying DNA repairing mechanism. Our in vitro and in vivo data strongly proclaims that THC-9-OG could not only abrogated 5FU mediated background EMT activation through stalling matrix degradation as well as murine 4T1 lung metastasis but also strongly diminished Rad-51 repairing mediator along with stimulation of γ-H2AX foci formation.

The combinatorial treatment (5FU + THC-9-OG) in Apc knockout colorectal carcinoma model conferred remission of the crypt progenitor phenotype which was prominently identified in 5FU treatment. Mechanistically, we demonstrated that 5FU plus THC-9-OG significantly attenuated major EMT inducer Vimentin via extensive ROS generation along with autophagy induction via LC3B I-II conversion and p62 degradation in a p-ATM dependent manner. Additionally, Cannabinoid receptor CB1 was responsible for abrogation of Vimentin since we found increase in the expression of γH2AX and decrease in vimentin expression in CB1 agonist (ACEA) plus 5FU treated cells.

Nutshell, our results unveil a new direction of Cannabinoid based combinatorial approach to control background EMT along with robust enhancing of DNA damage potential of sub-toxic concentration of 5FU resulting immense inhibition of distant metastasis coupled with triggering cell death in vitro and in vivo.”

https://pubmed.ncbi.nlm.nih.gov/38490521/

https://www.sciencedirect.com/science/article/abs/pii/S0006295224001096?via%3Dihub

Cannabinoids induce cell death in leukaemic cells through Parthanatos and PARP-related metabolic disruptions

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“Background: Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB.

Methods: Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo.

Results: We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists. WIN-treated mice, xenografted with AML cells, had better survival as compared to vehicle or cytarabine. DNA damage-related genes were affected upon exposure to WIN. Co-incubation with the PARP inhibitor Olaparib prevented WIN-induced cell death, suggesting PARP-mediated apoptosis which was further confirmed with the translocation of AIF to the nucleus observed in WIN-treated cells. Nicotinamide prevented WIN-related apoptosis, indicating NAD+ depletion. Finally, WIN altered glycolytic enzymes levels as well as the activity of G6PDH. These effects are reversed through PARP1 inhibition.

Conclusions: WIN-55 exerts an antileukemic effect through Parthanatos, leading to translocation of AIF to the nucleus and depletion of NAD+, which are reversed through PARP1 inhibition. It also induces metabolic disruptions. These effects are not observed in normal HSC.”

https://pubmed.ncbi.nlm.nih.gov/38461169/

“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/


Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation

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“To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] – 24.83, 95% confidence interval [95%CI] – 34.89, – 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD – 28.73, 95%CI – 45.43, – 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD – 4.85, 95%CI – 6.74, – 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents.

In human, treatment of cancer patients with medical cannabis (standardized MD – 0.19, 95%CI – 0.35, – 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity.

Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.”

https://pubmed.ncbi.nlm.nih.gov/38461339/

Cannabinoids in the treatment of glioblastoma

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“Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the median survival rate of GBM patients remains low and equals about 14 months. Due to this fact, there are intensive efforts to find drugs that would help combat GBM.

Nowadays cannabinoids are becoming more and more important in the field of cancer and not only because of their properties of antiemetic drugs during chemotherapy. These compounds may have a direct cytotoxic effect on cancer cells.

Studies indicate GBM has disturbances in the endocannabinoid system-changes in cannabinoid metabolism as well as in the cannabinoid receptor expression. The GBM cells show expression of cannabinoid receptors 1 and 2 (CB1R and CB2R), which mediate various actions of cannabinoids. Through these receptors, cannabinoids inhibit the proliferation and invasion of GBM cells, along with changing their morphology.

Cannabinoids also induce an intrinsic pathway of apoptosis in the tumor. Hence the use of cannabinoids in the treatment of GBM may be beneficial to the patients. So far, studies focusing on using cannabinoids in GBM therapy are mainly preclinical and involve cell lines and mice.

The results are promising and show cannabinoids inhibit GBM growth. Several clinical studies are also being carried out.

The preliminary results show good tolerance of cannabinoids and prolonged survival after administration of these drugs.

In this review, we describe the impact of cannabinoids on GBM and glioma cells in vitro and in animal studies. We also provide overview of clinical trials on using cannabinoids in the treatment of GBM.”

https://pubmed.ncbi.nlm.nih.gov/38457018/

https://link.springer.com/article/10.1007/s43440-024-00580-x

Supporting gut health with medicinal cannabis in people with advanced cancer: potential benefits and challenges

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“The side effects of cancer therapy continue to cause significant health and cost burden to the patient, their friends and family, and governments. A major barrier in the way in which these side effects are managed is the highly siloed mentality that results in a fragmented approach to symptom control. Increasingly, it is appreciated that many symptoms are manifestations of common underlying pathobiology, with changes in the gastrointestinal environment a key driver for many symptom sequelae. Breakdown of the mucosal barrier (mucositis) is a common and early side effect of many anti-cancer agents, known to contribute (in part) to a range of highly burdensome symptoms such as diarrhoea, nausea, vomiting, infection, malnutrition, fatigue, depression, and insomnia.

Here, we outline a rationale for how, based on its already documented effects on the gastrointestinal microenvironment, medicinal cannabis could be used to control mucositis and prevent the constellation of symptoms with which it is associated. We will provide a brief update on the current state of evidence on medicinal cannabis in cancer care and outline the potential benefits (and challenges) of using medicinal cannabis during active cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/37884682/

https://www.nature.com/articles/s41416-023-02466-w

Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives

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“Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management.

Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids.

Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials.

In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.”

https://pubmed.ncbi.nlm.nih.gov/38423660/

https://ar.iiarjournals.org/content/44/3/895

The effects of cannabidiol against Methotrexate-induced lung damage

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“Methotrexate (MTX) is a widely used medication for various cancers, yet its use is associated with adverse effects on organs, notably the lungs.

Cannabidiol (CBD), known for its antioxidant and anti-inflammatory properties, was investigated for its potential protective effects against MTX-induced lung injury.

Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (single 20 mg/kg intraperitoneal dose), MTX + CBD (single 20 mg/kg MTX with 0.1 ml of 5 mg/kg CBD for 7 days intraperitoneally) and CBD only (for 7 days). Lung tissues were analysed using histopathological, immunohistochemical and PCR methods after the study. Histopathological assessment of the MTX group revealed lung lesions like hyperemia, edema, inflammatory cell infiltration and epithelial cell loss. Immunohistochemical examination showed significant increases in Cas-3, tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) expressions. PCR analysis indicated elevated expressions of apoptotic peptidase activating factor 1 (Apaf 1), glucose-regulated protein 78 (GRP 78), CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome C (Cyt C), along with reduced B-cell lymphoma-2 (BCL 2) expressions in the MTX group, though not statistically significant.

Remarkably, CBD treatment reversed these findings.

This study highlights CBD’s potential in mitigating MTX-induced lung damage, suggesting its therapeutic promise.”

https://pubmed.ncbi.nlm.nih.gov/38388876/

“The findings from this study underscore the remarkable effectiveness of CBD in preventing histopathological damage within the lungs induced by MTX. The marked reduction observed in hyperemia, edema and infiltration, coupled with its notable reparative effects on epithelial loss, highlights the multifaceted benefits of CBD in mitigating pulmonary issues of MTX. Importantly, the statistical analysis revealed a significant improvement across all histopathological scoring parameters (p < 0.001). This reinforces the potential of CBD as a promising therapeutic agent for MTX-induced lung lesions and warrants further exploration in clinical settings. This study has demonstrated for the first time the reparative effects of CBD on the pathological findings induced by MTX in the lungs. There is now a need for novel and comprehensive research on the therapeutic utilization of CBD for this purpose.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13992

Cannabidiol protects C2C12 myotubes against cisplatin-induced atrophy by regulating oxidative stress

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“Cancer and chemotherapy can both cause cachexia, a complex multi-organ syndrome characterized by body weight loss, due to adipose tissue and skeletal muscle wasting. Changes in body weight and muscle mass are predictive of response to chemotherapy, incidence of treatment-related complications and, ultimately, patient survival, but there are currently still no clear therapeutic strategies to counteract cachexia.

Cannabidiol (CBD) is a bioactive phytocannabinoid produced from a plant named Cannabis sativa. In recent years, CBD has demonstrated beneficial effects on maintaining skeletal muscle mass, function and metabolism in models of muscular dystrophy or diet-induced obesity.

Here, we used a model of myotubes in culture to evaluate the potential beneficial effects of CBD on cisplatin-induced skeletal muscle wasting. 24-h cisplatin treatment resulted in a ≈30% reduction in myotube diameter, driven by a drastic reduction in protein synthesis rate and a twofold increase in proteolysis. 24-h cisplatin treatment also significantly increased myotube TBARS content, catalase activity and antioxidant system mRNA levels (GPX1, SOD1, SOD2 and CAT) indicating increased oxidative stress. 24-h cisplatin treatment also increased the mitochondrial protein content of NDUFB8, UQCRC2, COX4 and VDAC1, which are involved in mitochondrial respiration and control of apoptosis.

Importantly, CBD was found to antagonize chemotherapy-induced C2C12 myotube atrophy by promoting protein homeostasis and reducing oxidative stress. Our results show that CBD could be used as an adjuvant in the treatment of cancer cachexia to help maintain muscle mass and improve patient quality of life.”

https://pubmed.ncbi.nlm.nih.gov/38406827/

https://journals.physiology.org/doi/abs/10.1152/ajpcell.00622.2023

Cannabigerol Induces Autophagic Cell Death by Inhibiting EGFR-RAS Pathways in Human Pancreatic Ductal Adenocarcinoma Cell Lines

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“Pancreatic ductal adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis associated with this cancer is due to the absence of specific biomarkers, aggressiveness, and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that result in cancer-causing versions of the KRAS gene.

Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory properties.

Regarding the anticancer effect of CBG, up to now, there is only limited evidence in human cancers. To fill this gap, we investigated the effects of CBG on the PDAC cell lines, PANC-1 and MIAPaCa-2. The effect of CBG activity on cell viability, cell death, and EGFR-RAS-associated signaling was investigated. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate the effect of CBG on PDAC cell line viabilities. Annexin-V and Acridine orange staining, followed by cytofluorimetric analysis and Western blotting, were used to evaluate CBG’s effect on cell death. The modulation of EGFR-RAS-associated pathways was determined by Western blot analysis and a Milliplex multiplex assay. Moreover, by employing the MTT data and SynergyFinder Plus software analysis, the effect of the combination of CBG and chemotherapeutic drugs was determined.”

https://pubmed.ncbi.nlm.nih.gov/38396679/

“In conclusion, our results showed that CBG, a non-psychomimetic cannabinoid from Cannabis Sativa L., can induce an anticancer effect in two human PDAC cell lines, supporting the ability of cannabinoids to interfere with several pro-tumoral pathways.”

https://www.mdpi.com/1422-0067/25/4/2001

Cannabidiol activates MAPK pathway to induce apoptosis, paraptosis, and autophagy in colorectal cancer cells

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“Mitogen-activated protein kinase (MAPK) activation by natural compounds is known to be involved in the induction of apoptosis, paraptosis, and autophagy.

Cannabidiol (CBD), a bioactive compound found in Cannabis sativa, is endowed with many pharmacological activities. We investigated the cytotoxic effect of CBD in a panel of colorectal cancer (CRC) cells (HT-29, SW480, HCT-116, and HCT-15).

CBD induced significant cytotoxicity as evidenced by the results of MTT assay, live-dead assay, and flow cytometric analysis. Since CBD displayed cytotoxicity against CRC cells, we examined the effect of CBD on apoptosis, paraptosis, and autophagy. CBD decreased the expression of antiapoptotic proteins and increased the Annexin-V-positive as well as TUNEL-positive cells suggesting that CBD induces apoptosis. CBD increased the expression of ATF4 (activating transcription factor 4) and CHOP (CCAAT/enhancer-binding protein homologous protein), elevated endoplasmic reticulum stress, and enhanced reactive oxygen species levels indicating that CBD also promotes paraptosis. CBD also induced the expression of Atg7, phospho-Beclin-1, and LC3 suggesting that CBD also accelerates autophagy.

Since, the MAPK pathway is a common cascade that is involved in the regulation of apoptosis, paraptosis, and autophagy, we investigated the effect of CBD on the activation of JNK, p38, and ERK pathways. CBD activated all the forms of MAPK proteins and pharmacological inhibition of these proteins reverted the observed effects.

Our findings implied that CBD could induce CRC cell death by activating apoptosis, paraptosis, and autophagy through the activation of the MAPK pathway.”

https://pubmed.ncbi.nlm.nih.gov/38358093/

https://onlinelibrary.wiley.com/doi/10.1002/jcb.30537