Category Archives: Cancer

Antitumor Activity of Cannabinoids and Their Interaction with Chemotherapy: A Systematic Review and Meta-Analysis of Preclinical Evidence

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“Background: Cannabinoids are studied as anticancer agents, but their effects vary across tumors, compounds, and experimental settings, underscoring the need to define consistent patterns. Our objective was to map cannabinoid efficacy across cancer preclinical models and identify tumor settings with the greatest translational promise. 

Methods: The protocol was registered on PROSPERO (CRD42025543744); PubMed, Embase, and CENTRAL were searched on 4 April 2024 for in vitro and in vivo studies assessing cannabinoid antitumor effects alone or with chemotherapy versus vehicle or chemotherapy only. Random-effects models yielded pooled mean differences (MD) with 95% confidence intervals (CI). MDs of viable cells were calculated for in vitro assays and tumor volume (mm3) for in vivo studies. Reports of various compounds, cannabidiol (CBD), tetrahydrocannabinol (THC) or synthetic cannabinoids, were pooled. 

Results: We included 189 studies in the final analysis. In vitro, cannabinoids reduced cell viability modestly overall, with significant effects in glioblastoma (MD -18.77 [CI: -27.15; -10.39]) and a nonsignificant trend in breast cancer (MD -6.75 [CI: -13.90; 0.40]). For in vivo, monotherapy showed the most consistent efficacy in glioblastoma, significantly reducing tumor volume by MD -980.58 mm3; [CI: -1270.2; -690.88]. Addition to temozolomide produced a favorable but nonsignificant decrease of MD -220.65 mm3; [CI: -579.34; 138.03, vs. temozolomide]. In breast cancer, cannabinoids achieved smaller yet significant tumor reductions (MD -402.64 mm3); [CI: -671.84; -133.45]. Synthetic agents had the largest effect (MD -1295.19 mm3); [CI: -1664.33; -928.05] -CBD plus doxorubicin vs. doxorubicin). Lung cancer (MD -562.17 mm3); [CI: -693.99; -430.35] and prostate cancer (MD -1136.59 mm3); [95% CI: -1320.97; -952.21] also had a significant response, whereas colon, pancreatic, and hepatocellular carcinoma models showed inconsistent or null responses. 

Conclusions: Cannabinoids show promise as adjuncts in oncotherapy, particularly in glioblastoma and breast cancer, to enhance chemotherapy efficacy. These findings should be interpreted with caution given the high inter-study heterogeneity typical of preclinical research and should be considered hypothesis-generating, warranting further validation in standardized and clinically relevant models.”

https://pubmed.ncbi.nlm.nih.gov/42198443

“Cannabinoids have attracted growing attention in oncology as both supportive agents and potential direct antitumor therapies.”

“Beyond symptom management, preclinical studies over the past two decades have demonstrated that exogenous cannabinoids can influence key hallmarks of cancer, including proliferation, apoptosis, angiogenesis, and metastasis.”

“Notably, multiple studies indicate that cannabinoids can act synergistically with chemotherapy or radiotherapy, amplifying antitumor effects while potentially attenuating treatment-related toxicity. These interactions are clinically appealing, as they suggest a capacity to sensitize tumor cells to conventional agents and possibly enable dose reductions that limit systemic adverse effects.”

“Cannabinoids show emerging potential as adjuncts in oncological treatment, with relatively consistent signals observed particularly in glioblastoma and breast cancer models.”

https://www.mdpi.com/1424-8247/19/5/768

Identification of Changes in the Transcriptome Profile of Human Hepatoma HepG2 Cells Exposed to Combined Sorafenib and Cannabis Treatment

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“Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug-herb interactions with standard anticancer agents-namely sorafenib-remain unclear.

This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells.

Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups.

Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set of differentially expressed genes compared with single treatments.

Integrated enrichment analyses showed consistent activation of stress- and inflammation-related pathways, including tumor necrosis factor-α via nuclear factor-kappaB (TNF/NF-κB), mitogen-activated protein kinase (MAPK), janus kinase/signal transducers and activators of transcription (JAK-STAT), oxidative stress, and p53-mediated apoptosis, alongside suppression of metabolic and proliferative processes. While several pathways were shared across treatments, the combination group exhibited a more coordinated transcriptional response, including enrichment of integrated stress response, cytokine signaling, endoplasmic reticulum stress, and epigenetic regulation. These findings were supported by increased reactive oxygen species production and apoptosis, particularly in the combination group.

Overall, cannabis may potentiate sorafenib activity through enhanced cellular stress and anti-proliferative signaling.”

https://pubmed.ncbi.nlm.nih.gov/42196320

https://www.mdpi.com/1422-0067/27/10/4342

Computational Characterization of Nabilone-Induced Disruption of the CB2-HER2 Receptor Complex in HER2+ Breast Cancer

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“Human epidermal growth factor receptor 2-positive (HER2+) breast cancer, accounting for 15% to 20% of cases, is often resistant to treatment.

Delta-9-tetrahydrocannabinol (THC) disrupts HER2-cannabinoid receptor (2CB2) receptor complexes and inhibits HER2 activation.

This study evaluates whether Nabilone, a synthetic cannabinoid, can similarly disrupt HER2-CB2 interactions.

A CB2-HER2 complex model was generated via protein-protein docking. Three 1-µs molecular dynamics simulations (CB2-HER2, CB2-HER2-THC, CB2-HER2-Nabilone) were performed using the Schrodinger Desmond with membrane embedding and solvent. Structural stability (root mean square deviation [RMSD] and root mean square fluctuation [RMSF]), binding free energy (molecular mechanics/generalized born surface area [MM/GBSA]), and intracellular/extracellular distances between receptors were analyzed. Intermolecular interactions were assessed using the MAPIYA server.

Nabilone induced comparable structural instability to THC, with increased RMSD and RMSF. The MM/GBSA analysis showed Nabilone increased the binding free energy between CB2 and HER2, indicating stronger disruption. Intracellular and extracellular distances between CB2 and HER2 increased, especially intracellularly, with Nabilone. Intermolecular interaction analysis revealed that Nabilone decreased the number of contacts, particularly hydrophobic interactions, between CB2 and HER2.

Our in silico model predicts that Nabilone may disrupt the HER2-CB2 complex, suggesting a hypothesis that it could serve as a potential therapeutic agent. These computational findings warrant urgent experimental validation.”

https://pubmed.ncbi.nlm.nih.gov/42164472

“Cannabinoids have produced antitumor responses in preclinical models of cancer, including HER2+ BC, via binding and activating cannabinoid receptors, CB1 and CB2, both G-protein coupled receptors (GPCRs).”

“Nabilone, a synthetic analog of THC, was Food and Drug Administration (FDA)-approved in 1985 as a relief treatment for chemotherapy-related side effects, such as vomiting and nausea.”

“Our results indicate that Nabilone effectively disrupts the oncogenic CB2-HER2 complex, weakening the heterodimer interface through a mechanism of structural instability similar to THC but with superior binding affinity to CB2. While these findings rely on in silico predictions, limited by simulation timescales and simplified membrane models, they highlight a distinct opportunity for repurposing Nabilone from symptom management to active cancer therapy. We conclude that these data provide a robust theoretical framework that justifies urgent experimental validation in living systems to confirm the therapeutic potential of disrupting CB2-HER2 signaling.”

https://journals.sagepub.com/doi/10.1177/11779322261449332

Cannabidiol-Induced Tumor Cell Death: Molecular Mechanisms and Translational Perspectives in Cancer Therapy

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“Background: Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention as a potential anticancer agent because of its pleiotropic biological activities and favorable safety profile. However, the mechanisms by which CBD regulates tumor cell death and their therapeutic relevance remain incompletely understood.

Methods and results: This review summarizes current evidence on the molecular mechanisms by which CBD regulates tumor cell death across different cancer models. Available studies indicate that CBD exerts antitumor effects through multi-target and multi-pathway mechanisms involving oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, calcium homeostasis imbalance, and modulation of signaling networks such as PI3K/Akt/mTOR, MAPK, NF-κB, and PPARγ. Through these interconnected processes, CBD can induce apoptosis, autophagy, ferroptosis, pyroptosis, and cell cycle arrest in a context-dependent manner. Notably, CBD may activate multiple regulated cell death pathways simultaneously or sequentially within the same tumor model, reflecting a broader stress-response network rather than a single cytotoxic mechanism.

Therapeutic implications: By coordinately engaging multiple cell death pathways and modulating the tumor microenvironment, CBD provides mechanistic insights and potential opportunities for the development of novel anticancer strategies. However, current evidence remains predominantly preclinical, while challenges related to oral bioavailability, pharmacokinetic variability, dose optimization, and potential drug interactions continue to limit translational progress.

Conclusion: Collectively, available evidence suggests that CBD functions as a pleiotropic modulator of tumor cell fate rather than a classical single-target cytotoxic agent. Further mechanistic, pharmacological, and clinical studies are required to support the rational development of CBD-based anticancer therapies.”

https://pubmed.ncbi.nlm.nih.gov/42137120

“Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention as a potential anticancer agent due to its multimodal capacity to induce tumor cell death.”

“In conclusion, current evidence indicates that cannabidiol exerts antitumor effects through pleiotropic and context-dependent regulation of multiple cell death programs, including apoptosis, autophagy, ferroptosis, pyroptosis, and cell cycle arrest. By integrating oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, calcium imbalance, and diverse signaling networks, CBD reshapes tumor cell fate and provides a mechanistic basis for potential anticancer intervention.”

https://www.dovepress.com/cannabidiol-induced-tumor-cell-death-molecular-mechanisms-and-translat-peer-reviewed-fulltext-article-DDDT

Phytocannabinoids as epigenetic regulators: bridging DNA methylation and redox homeostasis in glioblastoma

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“Glioblastoma, a primary brain tumor of the CNS, is the most malignant lesion among gliomas. It has a median survival time of about 12-15 months after diagnosis and limited treatment options.

That neoplastic processes result from changes in the cell’s redox potential and the overproduction of reactive oxygen species. As a consequence, the epigenetic marker, m5C of DNA, is oxidized with ROS to 5-hydroxymethylcytosine, but guanosine is damaged to 8-oxo-dG, a general probe of oxidative stress. If so, the m5C, as well as 8-oxo-dG content in DNA, are subject to dynamic changes induced by environmental and endogenous cellular factors. These markers can be used to evaluate new therapeutic agents, among others.

Currently, there are no effective drugs against human glioblastoma.

Cannabinoids, small, lipophilic molecular compounds, are increasingly being studied for their antitumor properties.

Using the precise nucleotide post-labelling method and thin-layer chromatographic analysis we monitored the effect of CBD, THC, and CFE, as well as their combination with temozolomide, on changes of global m5C and 8-oxo-dG contents.

These results show that cannabinoids alone or in combination with the current standard glioblastoma chemotherapeutic, TMZ, inhibit the progression of GBM and could be used for its clinical treatment. The mechanism of cannabinoids’ actions on glioblastoma cells is also proposed.”

https://pubmed.ncbi.nlm.nih.gov/42118523

“Recently, cannabinoids have gained attention for their anticancer properties. They are found, among others, in Cannabis sativa L.”

“This paper shows that CBD and THC induce hypermethylation and proposes a novel mechanism of action for cannabinoids in glioblastoma.”

https://link.springer.com/article/10.1007/s13353-026-01070-x

Acute anti-proliferative and anti-migratory effects of cannabidiol on C6 rat glioma, SH-SY5Y human neuroblastoma, and HT22 mouse hippocampal neuronal cell cultures

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“Background: The treatment of central nervous system tumors remains challenging owing to their highly proliferative nature, aggressiveness, and poor prognosis. Additionally, existing treatment methods have several problems, including high risk of complications, systemic side effects, and impact on patients’ quality of life. Recently, cannabidiol (CBD), a non-psychoactive cannabinoid found in Cannabis sativa, has emerged as an alternative therapeutic medication because of its potential antitumor activity with fewer side effects.

Methods: We evaluated the cell viability, clonogenicity, migration, apoptotic nuclear morphology, and cell cycle phases of C6 rat glioma, SH-SY5Y human neuroblastoma, and HT22 immortalized mouse hippocampus neuronal cultures treated with CBD ranged between 0 and 10 μg/mL.

Results: CBD concentrations exceeding 5 μg/mL induced significant reductions in cell viability in C6 glioma and SH-SY5Y neuroblastoma cultures, accompanied by decreased clonogenicity in both cultures at 10 μg/mL. A scratch assay for cell migration revealed that 5 μg/mL CBD suppressed C6 glioma cell migration. Additionally, late apoptotic nuclear morphology was observed in C6 glioma cultures treated with 10 μg/mL cannabidiol. Similarly, HT22 hippocampal neuronal cultures exhibited decreased cell viability and clonogenicity, with apparent nuclear signs of apoptosis at CBD concentrations over 5 μg/mL. Notably, CBD disrupted HT22 cell migration at concentrations of 2.5 and 5 μg/mL. Proteomic profiling of C6 glioma revealed upregulation of ribosomal proteins, molecular chaperones, and modulators of cytoskeletal dynamics upon treatment with 1 μg/mL CBD. In comparison, treatment with 2.5 μg/mL CBD led to marked downregulation of endoplasmic reticulum chaperones, mitochondrial ATP synthase, and cytoskeletal regulators.

Conclusion: Our findings confirm the sensitivity of glioma, neuroblastoma, and hippocampal neuronal cultures to CBD, providing valuable insights for further research into its therapeutic potential against glioma, neuroblastoma, and neuronal disorders.”

https://pubmed.ncbi.nlm.nih.gov/42088408

“Our findings demonstrate that CBD exerts dose-dependent anti-proliferative effects across all three cell lines, with tumor cells and neuronal cells exhibiting comparable sensitivity at higher concentrations.”

https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2026.1727831/full

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