Category Archives: Cancer

Modulation of the endocannabinoid system reduces inflammatory signalling in canine mammary carcinoma cells

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“Background: Canine mammary carcinoma (CMC) is characterised by a chronic inflammatory microenvironment resembling human breast cancer; however, the upstream regulatory mechanisms driving this phenotype remain unclear. The endocannabinoid system (ECS) has emerged as a potential modulator of inflammation and tumour biology. This study investigated the role of the ECS in CMC and evaluated the anti-inflammatory effects of cannabidiol (CBD).

Methods: Primary cell cultures were established from surgically excised CMC tissues, with matched normal mammary epithelium used as controls. Basal mRNA expression of ECS-related receptors (CB1, CB2, transient receptor potential vanilloid 1 [TRPV1], G-protein-coupled receptor 55 [GPR55] and peroxisome proliferator-activated receptor alpha [PPAR-α]) and inflammatory mediators (COX-1, COX-2, interleukin [IL]-4, IL-6, IL-33, IL-17A, tumour necrosis factor-alpha [TNF-α] and LCN2) was assessed by reverse transcription quantitative polymerase chain reaction. Cytokine secretion (IL-6, IL-8, TNF-α and IL-17A) was quantified by enzyme-linked immunosorbent assay. Cell viability assays were performed to determine the 24-h IC50 of CBD (32 µM), and sub-cytotoxic concentrations (3, 10 and 20 µM) were subsequently applied for 24 h.

Results: Canine mammary carcinoma-derived cells exhibited significant overexpression of ECS receptors (CB1, CB2, TRPV1, GPR55 and PPAR-α) compared to normal controls. These cells also showed increased secretion of pro-inflammatory cytokines, including IL-6, IL-8, TNF-α and IL-17A. Treatment with CBD at 10-20 µM significantly downregulated key inflammatory genes, particularly COX-2, IL-6 and TNF-α, and reduced corresponding cytokine release without compromising cell viability.

Conclusion: The ECS is upregulated in CMC and appears to contribute to the inflammatory tumour microenvironment. Cannabidiol effectively attenuates this inflammatory phenotype at sub-cytotoxic concentrations, supporting its potential as a therapeutic agent in CMC.”

https://pubmed.ncbi.nlm.nih.gov/42078490

“These findings may also have relevant implications for human health, as CMC shares key molecular and pathological features with human breast cancer. Therefore, the modulation of ECS-related pathways observed in this study may reflect conserved mechanisms that could be exploited for the development of novel anti-inflammatory and anti-tumour strategies in human oncology.”

https://bvajournals.onlinelibrary.wiley.com/doi/10.1002/vro2.70034

The Effect of Cannabidiol on Cancer-Pathway Genes in Doxorubicin-Sensitive and Resistant Breast Cancer Cells

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“Purpose: Cannabidiol (CBD) is a primary bioactive, non-intoxicating cannabinoid found in the cannabis plant. Studies have shown that CBD causes anticancer activity by inhibiting the expression of growth factors and inducing apoptosis, leading to cell cycle arrest. In this study, we aimed to determine how CBD influences the expression of genes that affect cancer pathways in doxorubicin-sensitive (MCF-7) and doxorubicin-resistant (MCF-7/Adr) breast cancer cells. 

Materials and Methods: IC50 concentrations of CBD in MCF-7 and MCF-7/Adr cell lines were determined by the MTT cell cytotoxicity assay. RNA isolation and subsequent cDNA synthesis were performed for qPCR experiments with the determined IC50 values. The effects of CBD on the cell cycle and apoptosis were studied using flow cytometry. IC50 values of CBD were determined in MCF-7 and MCF-7/Adr breast cancer cell lines at eight different concentrations and at three different incubation periods (24 h, 48 h, and 72 h) with different doses. RT-qPCR was used to investigate the molecular mechanisms underlying the expression of genes involved in cancer pathway analysis. 

Results: Treatment with CBD at concentrations of 17.57 μM (MCF-7) and 11.41 μM (MCF-7/Adr) for 48 h decreased colony formation, induced apoptosis, and inhibited cell invasion in both cell lines. In addition, we observed significant alterations of angiogenesis, apoptosis, cell cycle, cellular senescence, DNA damage and repair, epithelial-to-mesenchymal transition, hypoxia, metabolism, telomeres, and telomerase in both cell lines. 

Conclusions: Our research indicates that CBD could be an effective natural bioactive compound for breast cancer treatment, inhibiting tumor cell proliferation and inducing apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/42075870

“The plant Cannabis sativa has been used medicinally for several thousand years.”

“These findings support the relevance of CBD as a potential therapeutic agent in breast cancer and provide a basis for further investigation “

https://www.mdpi.com/1424-8247/19/4/615

Cannabinoid-Driven Rewiring of GPCR and Ion Channel Signaling in Lung Cancer

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“Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response.

Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks.

This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity.

Special attention is given to G protein-coupled receptor-ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted.

Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer.”

https://pubmed.ncbi.nlm.nih.gov/42072396

“While challenges remain (optimal dosing, patient selection, and regulatory hurdles), the insight that can simultaneously target GPCRs and ion channels to cripple lung cancer is a paradigm shift. The convergence of cancer signaling biology with cannabinoid pharmacology opens up exciting possibilities for combination treatments that might tackle tumor resistance and recurrence. In summary, cannabinoid-driven modulation of GPCR and ion channel signaling represents a promising multi-pronged strategy against lung cancer, warranting further investigation and translation into clinical trials.”

https://www.mdpi.com/2227-9059/14/4/856

Cannabinoid receptors orchestrate distinct anti-tumour pathways in gastric cancer via and beyond specialized pro-resolving mediators

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“Endocannabinoids (ECS) and specialized pro-resolving mediators (SPMs) are both lipid-based compounds, but differ significantly in origin, mechanisms, and functions. Their mechanistic interaction in cancer remains undefined, particularly in gastric cancer (GC). Several interconnections have been described between these two “bioactive lipids” involved in inflammation resolution, homeostatic and anti-tumour functions.

Cannabinoid signalling can modulate SPM biosynthesis in immune cells, thus we investigated whether this crosstalk operates in GC cells, and whether SPMs mediate part of the anti-tumour activity of cannabinoid receptors.

Using synthetic and selective agonists for the cannabinoid G-protein-coupled receptors CB1 and CB2 (ACEA and JWH133, respectively), we found that receptor activation in GC cells (AGS and MKN45) sustains the synthesis of two SPMs, Resolvin D1 and Lipoxin B4, which in turn suppresses the angiogenic potential of GC cells. These CB1/CB2-driven activities required a SRC/MAPK signalling. At physiological concentrations, these SPMs further enhanced the binding affinity of ACEA and JWH133 for CB1 and CB2, indicating a functional crosstalk between the two systems.

Beyond angiogenesis, CB1/2 stimulation reduced cell proliferation and viability, induced apoptosis, impaired the migration and the epithelial-to-mesenchymal program in GC cells. Only CB2 activation reduced the stemness properties of GC cells. Interestingly, while the anti-angiogenic properties of CB1 and CB2 required SPM production, their other anti-tumour actions were independent of the pro-resolving pathway.

Our results extend the current knowledge of the endocannabinoid system by defining a new dual mechanism, SPM-dependent and SPM-independent, that restrains GC progression and identify the ECS-SPM axis as a potential target for therapeutic intervention.”

https://pubmed.ncbi.nlm.nih.gov/41775095

“CB1 and CB2 activation sustain potent anti-tumour effects in gastric cancer (GC).”

“In conclusion, this work demonstrates that cannabinoid receptor activation restrains gastric cancer cell proliferation, migration, stemness, and angiogenesis through both SPM-dependent and SPM-independent mechanisms. By linking ECS activation to pro-resolving lipid metabolism via SRC-ERK signalling, our data position CB1 and CB2 as regulators of tumour control rather than progression. These findings open the way for preclinical in vivo studies aimed at exploiting cannabinoid-SPM crosstalk as a novel therapeutic axis in gastric cancer.”

https://www.sciencedirect.com/science/article/pii/S0753332226002192?via%3Dihub

Antiproliferative Effects of Cannabinoids and Cisplatin in Cervical Cancer Cells

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“Introduction: Cervical cancer remains a leading cause of cancer-related mortality among women globally, particularly in low- and middle-income countries. Cisplatin, a standard chemotherapeutic agent, is limited by severe toxicities and chemoresistance. This study aimed to assess the effects of cisplatin in combination with phytocannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on cell proliferation, morphology, cell cycle progression, cell death, and DNA damage.

Methods: Synergistic interactions between THC, CBD, and cisplatin were assessed in HeLa, SiHa, and MCF-12A cells using the checkerboard assay and SRB assay. Cell morphology, cell cycle progression, apoptosis induction, autophagic activity, and DNA repair gene expression were evaluated using various techniques.

Results: The THC-CBD-cisplatin combination exhibited the strongest apoptotic response in cancer cells (HeLa 53%, SiHa 58%), while minimally affecting MCF-12A cells (32%). Cannabinoid co-treatment amplified the antiproliferative and pro-apoptotic effects of cisplatin in HeLa and SiHa cells. The triple combination induced a G2/M arrest in HeLa cells and sub-G1 accumulation in SiHa cells. Autophagic activity, indicated by LC3B puncta formation, increased in HeLa and SiHa cells following THC and CBD exposure. DNA repair genes XRCC1 and RAD51 were downregulated by the cannabinoid-cisplatin combination.

Conclusion: These findings demonstrate that combining THC and CBD with cisplatin results in enhanced and mechanistically diverse anticancer effects, with a higher degree of selectivity for cervical cancer cells compared to non-cancerous MCF-12A cells by inducing apoptosis and autophagy while inhibiting DNA repair capacity. This study highlights the potential of cannabinoid-based combination therapies as a promising approach for cervical cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/42055476

“Cannabinoids, a diverse group of bioactive compounds from the cannabis plant, have been shown to inhibit cancer cell proliferation through mechanisms such as inducing apoptosis, arresting the cell cycle, and inhibiting angiogenesis.”

“This study demonstrates that the combination of cannabinoids, specifically THC and CBD, with cisplatin results in enhanced, selective, and mechanistically diverse anticancer effects in cervical cancer cells. The combined treatment induces apoptosis and autophagy while inhibiting DNA repair capacity, leading to significant cytotoxicity against cancer cells and minimizing damage to normal cells. These findings underscore the potential of cannabinoid-based combination therapies as a promising and safer approach for cervical cancer treatment.”

https://onlinelibrary.wiley.com/doi/10.1002/cnr2.70561

Evaluation of Dronabinol to Decrease Opioid Use for Cancer-Induced Bone Pain

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“Background: Bone metastases (BM) from breast cancer cause significant cancer-induced bone pain (CIBP). Management of CIBP is primarily with opioids, which have notable side effects. In preclinical models, cannabinoid receptor (CB)2 and CB1 agonists were shown to decrease CIBP and bone degradation. We hypothesized that the addition of CB2/CB1 agonists would decrease opioid requirements in patients with BM.

Methods: We conducted a single-arm study among breast cancer patients with BM on opioid therapy. Patients were treated with 10 mg dronabinol BID for 8 weeks. Our primary objective was to determine the proportion who decreased their opioid use by ≥ 20%. Participants completed the Brief Pain Inventory and the European Organization for Research and Treatment of Cancer quality of life questionnaires before and after treatment. Pre- and post-treatment blood and urine were collected for analysis of biomarkers of bone remodeling.

Results: We enrolled 14 evaluable patients, and 4 decreased opioid use by ≥ 20%, meeting the primary endpoint. Patients reported significant improvements in pain severity, interference scores, quality of life, and insomnia. There was one grade 3 adverse event (dizziness) related to the study drug. A significant decrease was noted in serum C-terminal telopeptide levels with therapy.

Conclusion: Our pilot study shows that the addition of dronabinol resulted in decreased opioid requirements for CIBP. Patient-reported outcomes also demonstrated improved pain and QOL with addition of dronabinol. Our results are promising and warrant further investigation into novel analgesics for CIBP to decrease opioid use.”

https://pubmed.ncbi.nlm.nih.gov/42050177

https://academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyag163/8664403

“Dronabinol, sold under the brand names Marinol and Syndros, is the generic name for the molecule of (−)-trans-Δ9-tetrahydrocannabinol (THC) in the pharmaceutical context. It has indications as an appetite stimulant and antiemetic and is approved by the US Food and Drug Administration (FDA) as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.”

Cannabidiol potentiates olaparib-induced cytotoxicity through cell cycle arrest and DNA damage modulation in breast cancer cells

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“Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive nature and limited treatment options, while therapeutic resistance in estrogen receptor-positive (ER+) breast cancer continues to limit treatment efficacy.

Although olaparib is primarily effective in BRCA-mutated cancers, its activity in BRCA-wild type (BRCA-wt) tumors is limited. Therefore, this study aimed to investigate whether cannabidiol (CBD) can enhance the response of BRCA-wt breast cancer cells to PARP inhibition.

The effects of olaparib (OLAP) and CBD, alone and in combination, were evaluated in MDA-MB-231 (TNBC) and MCF-7 (ER+) cell lines using comprehensive two-dimensional (2D) mechanistic analyses and three-dimensional (3D) spheroid models, including HCC-70 cells to extend TNBC validation.

The results demonstrate that combined OLAP and CBD treatment enhanced cytotoxic effects compared to single treatments, with more pronounced responses observed in 3D spheroid models, particularly in TNBC models. Flow cytometry and caspase 3/7 assays indicated increased apoptosis and G2​/M phase arrest following combination treatment. Gene expression analysis revealed downregulation of key DNA damage response and cell cycle-related genes (ATM, ATR, BRCA1/2, RAD51, and CDK1/2/4/6), supporting a role for cell cycle arrest and DNA damage modulation in mediating these effects. Functional assays showed reduced colony formation and migratory capacity, although these effects may reflect both cytotoxic and cytostatic responses under the selected experimental conditions.

Overall, these findings suggest that CBD may enhance the efficacy of olaparib in BRCA-wt breast cancer models and highlight its potential as a combinational therapeutic strategy in breast cancer treatment.”

“Cannabinoids have been reported to enhance the effects of conventional cancer treatments, including chemotherapy and radiotherapy, thereby improving therapeutic efficacy while potentially reducing treatment-related toxicity.”

“CBD, in particular, has shown promising antitumor activity in triple-negative breast cancer (TNBC) by inducing apoptosis, autophagy, and oxidative stress through modulation of signaling pathways such as AKT/mTOR.”

https://link.springer.com/article/10.1007/s11010-026-05550-w

Inhibition of extracellular vesicle secretion by cannabidiol: A promising approach for oral squamous cell carcinoma therapy

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“Cannabidiol (CBD), a bioactive phytochemical derived from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and emerging antitumor properties.

Oral squamous cell carcinoma (OSCC), the most common oral cancer, remains challenging to treat due to its aggressive nature and limited therapeutic options. Extracellular vesicles (EVs) have been increasingly recognized as key mediators of tumor progression, facilitating intercellular communication, remodeling the tumor microenvironment (TME), and promoting metastasis, angiogenesis, and chemoresistance in OSCC.

This review discusses the pharmacological properties of CBD, including its bioavailability limitations, multi-target mechanisms, and potential for combination therapy. Notably, we explore the hypothesis that CBD may exert antitumor effects through modulation of EV secretion-a novel and underexplored mechanism in OSCC. Although direct evidence in OSCC models remains limited, studies in non-OSCC systems suggest that CBD influences EV biogenesis and release via pathways involving Wnt/β-catenin, STAT3 signaling, and mitochondrial calcium homeostasis.

Based on these findings, we propose a hypothetical framework linking CBD-mediated EV modulation to OSCC therapy. Despite its therapeutic promise, the clinical translation of CBD faces key hurdles, including poorly characterized mechanisms of EV regulation in OSCC, a lack of targeted delivery systems that compromises specificity and bioavailability, and a general scarcity of OSCC-specific evidence.

This review underscores the urgent need for future research to prioritize long-term evaluations, explore synergistic CBD-drug combinations, develop advanced CBD delivery systems, and assess its dual role in tumor suppression and pain management to enable clinical use.”

https://pubmed.ncbi.nlm.nih.gov/41966486

“Cannabidiol (CBD) is a non-psychoactive phytocannabinoid derived from Cannabis sativa L., characterized by low toxicity and a broad spectrum of pharmacological activities.These include antiepileptic, anti-inflammatory, neuroprotective, antiemetic, anticonvulsant, anxiolytic, antispasmodic, and anticancer effects.”

https://www.sciencedirect.com/science/article/pii/S0006295226002819?via%3Dihub

The iron fist of nature: Cannabinoid derivatives alter iron homeostasis and activate ferroptotic pathways in glioblastoma cells

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“Glioblastoma multiforme is the most commonly diagnosed type of brain tumor, with a poor prognosis and a high rate of recurrence. Because of its highly aggressive nature and the lack of efficient treatment options, novel therapeutic strategies are needed.

Ferroptosis is an iron-dependent, unique type of cell death, which provides an alternative way to eradicate cancer cells that are resistant to apoptosis and other cell death mechanisms.

CP55-940 (CP) and WIN 55212-2 (WIN) are synthetic cannabinoid receptor agonists with various biological activities, including neuroprotective and anticancer effects; however, their mechanism of action has not been fully uncovered.

In the present study, the potential of CP and WIN in glioblastoma cells was investigated.

Cell viability was determined with the MTT assay. Labile iron pool and reactive oxygen species generation were visualized with confocal microscopy. Malondialdehyde assay was performed to detect lipid peroxidation. Gene expressions of ferroptotic hallmarks, glutathione peroxidase-4, and transferrin receptor 1 were determined by RT-qPCR. Protein expression levels of iron-responsive element-binding protein 2, solute carrier family 7 member 11, and glutathione peroxidase-4 were analyzed by western blotting.

Results demonstrated that CP and WIN significantly induce ferroptotic pathways in glioblastoma cells via increased oxidative stress, labile iron pool, and lipid peroxidation. Furthermore, it was determined for the first time that both compounds significantly upregulate the transferrin receptor 1 gene expression.

In conclusion, the present study demonstrated for the first time that cannabinoid derivatives CP and WIN alter iron regulation and initiate ferroptosis in glioblastoma cells, rendering them potential candidates in therapy.

SIGNIFICANCE STATEMENT: We explored the ferroptotic activity of cannabinoid derivatives (CP and WIN) in glioblastoma cells for the first time. Additionally, we report for the first time that cannabinoid derivatives alter cellular iron levels, causing increased labile iron pool via upregulating the transferrin gene significantly.”

https://pubmed.ncbi.nlm.nih.gov/41962357

https://jpet.aspetjournals.org/article/S0022-3565(26)00518-5/abstract

“CP 55,940 is a synthetic cannabinoid which mimics the effects of naturally occurring THC (one of the psychoactive compounds found in cannabis). CP 55,940 was created by Pfizer in 1974 but was never marketed. It is currently used as a research tool to study the endocannabinoid system.”

“WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.”

Cannabis use among cancer survivors: a systematic review and meta-analysis

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“The use of medical cannabis has been receiving growing attention as a potential therapeutic option for a diverse range of medical conditions, including cancer-related symptoms. The aim of this study was to estimate the prevalence of cannabis use among cancer survivors (post-treatment survivorship populations) and, secondarily, to compare these estimates with non-cancer control groups.

Methods

Following PRISMA guidelines (PROSPERO CRD42024510013), we searched PubMed, Scopus, PsycINFO, Web of Science, CINAHL Complete, and grey literature through November 1, 2025. We included observational studies reporting the prevalence of cannabis use among cancer survivors (i.e., individuals with a history of cancer in survivorship/follow-up settings), regardless of whether a comparison group was available. In studies with comparator groups, controls were individuals without a history of cancer drawn from general population or other non-cancer reference samples. Random-effects (REML) models were used to pool prevalence estimates, while comparative odds ratios (ORs) were analyzed as a secondary outcome.

Results

Twenty-seven studies (176,072 participants; 21,025 cancer survivors and 155,047 controls) were included. Among survivors, pooled prevalences of cannabis use were 36.39% (95% CI 24.53–48.25) for lifetime use and 15.2% (95% CI 10.64–19.76) for past 30-day use, with lower estimates for current use (11.72%; 95% CI 5.02–18.43) and past-year use (7.96%; 95% CI 2.22–13.70). In studies with non-cancer controls, cancer survivors had lower odds of past 30-day use (OR 0.54; 95% CI 0.35–0.85; p = 0.01), however, no statistically significant differences were observed for current use (OR 0.93; 95% CI 0.79–1.10; p = 0.42), past-year (OR 0.40; 95% CI 0.12–1.30; p = 0.13), and lifetime cannabis use (OR 0.98; 95% CI 0.70–1.37; p = 0.92).

Conclusion

Cannabis use is common among cancer survivors. Compared with non-cancer populations, survivors showed lower odds of recent (past 30-day) use, while no statistically significant differences were observed for current, past-year, or lifetime cannabis use. These findings underscore the need for open, evidence-based counseling about potential benefits, risks, and safe use in survivorship care.”

https://pubmed.ncbi.nlm.nih.gov/41923168

https://link.springer.com/article/10.1186/s13690-026-01911-5