Category Archives: Cancer

Hemp-Derived Extracellular Vesicles: A Novel Frontier in Nanomedicine and Therapeutics

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“While mammalian-derived extracellular vesicles (EVs) face significant challenges in clinical translation due to scalability, cost, and safety, plant-derived EVs (PDEVs) have emerged as a promising alternative.

This review focuses on EVs derived from hemp (Cannabis sativa L.), or HEVs, a particularly compelling source that combines the general benefits of PDEVs, such as improved safety and scalability, with a unique, inherent therapeutic cargo.

HEVs are naturally enriched with a potent mix of cannabinoids, terpenes, and flavonoids, which may enhance therapeutic outcomes through synergistic interactions-a phenomenon known as the ‘entourage effect.’

Preclinical studies already demonstrate their potential, showing significant anti-cancer effects against aggressive tumors like glioblastoma, along with neuroprotective and anti-inflammatory properties.

However, the critical challenge hindering their clinical application is the lack of standardized, GMP (Good Manufacturing Practice)-compliant manufacturing protocols to address the inherent biochemical variability of the source material.

Overcoming these obstacles will be vital to unlocking the potential of HEVs as a novel, scalable frontier in nanomedicine.”

https://pubmed.ncbi.nlm.nih.gov/41787227

https://link.springer.com/article/10.1007/s40259-026-00766-0

Cannabidiol-induced cellular and matrix-associated responses in primary equine sarcoid cells

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“Background: Sarcoids are locally invasive skin tumors in equids, associated with bovine papillomavirus.

Hypothesis/objectives: Address potential applications of cannabidiol (CBD) in veterinary medicine. We evaluated the response of equine sarcoid cells to CBD in vitro, focusing on viability, invasiveness, and matrix remodeling.

Animals: Three primary sarcoid cell lines.

Methods: Cells were treated with CBD (20, 6.75, 2.25, 0.75 μM) and incubated for 6, 24, 48, 72 hours. Cell viability, cytotoxicity, and apoptosis were assessed using the ApoTox-Glo Assay. Based on these results, further analyses were performed for selected conditions only, including the assessment of cell invasiveness using the ECMatrix™ Cell Invasion Assay and the quantification of matrix metalloproteinase (MMP)-1, -2, and -9 in the culture medium by ELISA.

Results: Treatment with CBD affected cell viability, cytotoxicity, and apoptosis. At 48 hours, apoptosis (measured as caspase 3/7 activity) reached 49.5% and further increased to 75% at 72 hours. Marked cytotoxicity (>96%) and decreased viability were observed at 72 hours. Cannabidiol also significantly decreased MMP-1 concentration by 48.9% at 24 hours and MMP-2 concentrations by 84% at 6 hours. Concentrations of MMP-9 also decreased by 37.2% and 45.3% at 6 and 48 hours, respectively, after treatment with 20 μM. Despite observed decreases in cell invasiveness ranging from 34% to 59% after 24 hours, these changes were not significant.

Conclusions and clinical importance: Our findings support further investigation of CBD’s role in extracellular matrix modulation in sarcoid tumors.”

https://pubmed.ncbi.nlm.nih.gov/41742517

“Overall, equine sarcoid cells exhibit clear biological responsiveness to CBD, supporting its relevance as a modulator of matrix remodeling and invasive potential in this tumor model.”

https://academic.oup.com/jvim/article/40/1/aalaf015/8429746?login=false

Potential therapeutic role of Cannabidiol and vitamin D in Hepatocellular carcinoma: evidence from in vitro studies

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“Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. Natural compounds with anticancer properties have gained increasing attention.

Cannabidiol (CBD) and Vitamin D have individually been reported to exert anti-proliferative and pro-apoptotic effects in various cancer models.

Methods and results

The effects of Vitamin D and CBD, alone and in combination, were investigated in two human HCC cell lines, Hep3B and Huh7. Cell viability was assessed using MTS assays, and drug interactions were evaluated by the Chou–Talalay method. Apoptosis, cell cycle progression, and molecular changes related to apoptosis, autophagy, cell proliferation, and DNA damage response were analyzed by flow cytometry and real-time PCR. Combined treatment with Vitamin D and CBD resulted in a synergistic reduction in cell viability in both cell lines, with lower IC₅₀ values compared to single treatments. The combination enhanced apoptotic signaling and inhibited cell proliferation in a cell line–dependent manner. In Hep3B cells, combined treatment induced G1 phase arrest, modulation of autophagy-related genes, and alterations in DNA damage response pathways, whereas Huh7 cells exhibited distinct transcriptional responses.

Conclusions

These findings demonstrate that the combination of Vitamin D and CBD exerts enhanced anticancer effects in HCC cells in vitro. This study provides mechanistic insight supporting further investigation of Vitamin D and CBD as a potential combinatorial therapeutic approach for HCC.”

https://link.springer.com/article/10.1007/s11033-026-11555-x

Cannabinoids and the autophagy-related signaling in brain Tumors: From mechanistic insights to therapeutic Frontiers in glioblastoma

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“Glioblastoma multiforme (GBM) is a very aggressive primary brain tumor in adults, characterized by extensive infiltration, therapeutic resistance, and a dismal prognosis, with an average life of roughly 14 months. Despite advances in oncology, therapeutic progress for GBM has been limited, prompting intensive efforts to discover novel interventions.

Cannabinoids, beyond their established role as antiemetics during chemotherapy and radiotherapy, have emerged as potential cytotoxic agents against neoplastic cells.

Recent studies demonstrate that GBM harbors alterations in the endocannabinoid system, including changes in cannabinoid metabolism and receptor (CB1R, CB2R) expression. Engagement of these receptors by cannabinoids can suppress proliferation, invasion, and induce morphological changes in GBM cells, also activating intrinsic autophagy pathways.

Autophagy, a process central to cellular degradation and recycling, exerts dual roles in tumor survival and apoptosis, critically modulated by cannabinoids in glioblastoma. Preclinical work in cell lines and animal models suggests that both cannabinoids and pharmacologic modulators of autophagy reduce GBM proliferation and enhance responsiveness to chemotherapeutics. Early clinical studies indicate favorable safety profiles and potential survival benefits.

This review synthesizes the molecular mechanisms and signaling pathways underlying cannabinoid-induced autophagy and anticancer activity, and summarizes the current preclinical and clinical research on cannabinoid-based therapies for GBM.”

https://pubmed.ncbi.nlm.nih.gov/41679657

“This review demonstrates that cannabinoids, an emerging class of potential antitumor agents, promote autophagy in cancer cells and enhance the cytotoxic effects of these compounds. The study demonstrated that THC facilitates autophagy and apoptosis in diverse cancer cell types, whereas nontransformed astrocytes display resistance to cannabinoid-induced cytotoxicity. “

https://www.sciencedirect.com/science/article/abs/pii/S0006295226001127?via%3Dihub


Pharmacokinetic studies and synergistic antitumor effects of cannabichromene and cannabidiol in drug-resistant breast cancers

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“Triple-negative breast cancer (TNBC) is highly aggressive with limited treatment options, and resistance to doxorubicin (DOX) further compromises outcomes.

Cannabinoids such as cannabichromene (CBC) and cannabidiol (CBD) possess anticancer properties, but their combined effects in resistant TNBC remain unexplored. This study evaluated the antitumor efficacy of a CBC + CBD combination against DOX-resistant (DOX-RT) TNBC using in vitro, in vivo, and pharmacokinetic models.

Cytotoxicity was assessed in DOX-RT MDA-MB-231 cells using 2D and 3D assays, with synergy confirmed by combination index (CI) analysis. Cell cycle and invasion assays were performed. Xenograft studies were conducted in BALB/c nude mice bearing DOX-RT tumors treated intraperitoneally with CBC (10 mg/kg), CBD (20 mg/kg), or CBC + CBD. Pharmacokinetics were evaluated in rats, complemented by GastroPlus™ simulations.

CBC + CBD synergistically inhibited cell growth induced G0/G1 arrest, and reduced invasiveness by ~ 55% in a Transwell Matrigel invasion assay. In xenografts, combination therapy reduced tumor volume by two-folds compared to single treatments and fourfolds versus control. Western blotting revealed downregulation of MEK/ERK, PI3K/AKT/mTOR, Cyclin D1, CDK6, SOD2, and NF-κB. Pharmacokinetic studies showed co-administration increased Cmax and AUC without altering Tmax, supported by simulations predicting enhanced jejunal absorption. CBC + CBD co-therapy demonstrates synergistic efficacy against resistant TNBC by inhibiting oncogenic pathways and enhancing systemic exposure.

This first study of its kind highlights CBC + CBD as a promising strategy to overcome DOX resistance in TNBC.”

https://pubmed.ncbi.nlm.nih.gov/41670942

https://link.springer.com/article/10.1007/s13346-026-02057-1

Cannabidiol modulates exosomal miRNA networks to enhance Imatinib mesylate response in chronic myelogenous leukemia

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“Background/objectives: Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease driven by the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKIs) such as Imatinib mesylate have dramatically improved patient outcomes, yet resistance remains a major obstacle to long-term efficacy. Exosomes, as carriers of bioactive molecules including miRNAs, are increasingly recognized as mediators of drug resistance. CBD has demonstrated antiproliferative and pro-apoptotic effects in several cancer models, but its potential to modulate Imatinib sensitivity or resistance in CML remains unclear. This study aimed to investigate exosomal miRNA signatures associated with Imatinib sensitivity and resistance in the context of treatment with Cannabidiol (CBD), Imatinib mesylate (IM), and their combination.

Methods: Following treatment with CBD, IM, and CBD+IM, exosomal miRNA profiles in Imatinib-sensitive (K-562S) and Imatinib-resistant (K-562 R) cell lines were analyzed. Gene Ontology (GO) enrichment and semantic clustering was performed.

Results: CBD activated tumor-suppressive and apoptosis-related miRNAs in K-562S cells, whereas K-562 R cells showed a dual response involving oncogenic miRNAs and metabolic regulators. IM induced suppressive cascades in K-562S but caused loss of canonical tumor suppressors in K-562 R. CBD+IM produced synergistic amplification of apoptotic and differentiation-related pathways in sensitive cells, while resistant cells showed partial restoration of apoptosis but persistent loss of tumor suppressors. HMGB1-associated miRNAs were identified, of which suppressed were miR-615-5p, miR-4435, let-7 g-3p, and the miR-548 family, alongside upregulated miR-3191-3p and miR-33a-5p.

Conclusions: Circulating miRNAs are valuable biomarkers for TKI resistance in CML. Targeting HMGB1-associated miRNAs, together with combined CBD and IM treatment, may help re-establish apoptotic regulation and overcome resistance mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41657764

https://www.sciencedirect.com/science/article/pii/S2699940426000020?via%3Dihub

Hemp seed extract exerts cytostatic effects through metabolic stress and autophagy modulation in malignant cells

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“Phytocannabinoids from Cannabis sativa L. exhibit anticancer activity, but how the polar fraction from cold-pressed hemp seed oil derived from industrial cultivars lacking Δ9-THC affects cell proliferation remains unclear.

Here, we characterized the phenolic composition of the Oil Polar Extract (OPE) from the Codimono cultivar and evaluated its effects on cancer cells. In HT-29 colorectal cells, OPE induced metabolic stress, decreasing ATP by ~ 40%, activating AMPK, and disrupting autophagic flux. This stress led to G1 phase cell cycle arrest without triggering apoptosis.

Notably, pharmacological inhibition of autophagy with chloroquine enhanced the antiproliferative effects of the extract by ~ 30%, indicating that autophagy serves a cytoprotective role.

These findings identify OPE as a metabolic modulator capable of inducing an AMPK-dependent cytostatic effect in colorectal cancer cells, supporting its potential as a non-psychotropic, plant-derived anticancer strategy and as a candidate for combination therapies with autophagy inhibitors.”

https://pubmed.ncbi.nlm.nih.gov/41620507

https://www.nature.com/articles/s41598-026-37119-4

HER2-dependent paraptosis and ferroptosis induction by cannabidiol in breast cancer cells

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“HER2 (human epidermal growth factor receptor 2) is a well-established oncogenic driver and therapeutic target in breast cancer.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has demonstrated anticancer potential, yet its mechanisms of action in HER2-positive breast cancer remain insufficiently characterized.

In this study, we examined the effects of CBD on HER2-positive (SK-BR-3, BT-474) and HER2-negative (MCF-7, MDA-MB-231) breast cancer cell lines, with a focus on its interaction with HER2.

CBD selectively reduced the viability of HER2-positive cells, an effect associated with increased intracellular reactive oxygen species (ROS) and a marked reduction in HER2 protein levels. Mechanistically, CBD triggered non-apoptotic cell death pathways, including paraptosis and ferroptosis, as indicated by the modulation of specific molecular markers such as reduced Alix and elevated ATF4 and CHOP for paraptosis, and downregulated GPX4 and SLC7A11 with upregulated TFRC for ferroptosis. HER2 knockdown attenuated CBD-induced cytotoxicity, while HER2 overexpression sensitized cells to CBD, underscoring the HER2-dependence of these effects. Molecular docking predicts the binding conformation and key interactions of ligand with target proteins providing initial insights into potential molecular recognition. Subsequently, molecular dynamics simulations extend this analysis by assessing the stability, flexibility, and energetic characteristics of the ligand-protein complex within a dynamic biological environment.

These findings support a model in which CBD downregulates HER2 and, in a HER2-dependent context, promotes paraptosis and ferroptosis. In addition, docking and molecular dynamics analyses suggested a potential interaction between CBD and HER2, providing mechanistic insights into possible molecular recognition relevant to HER2-positive breast cancer.”

https://pubmed.ncbi.nlm.nih.gov/41621547

“These results suggest that CBD targets HER2, offering a new therapeutic strategy for HER2-positive breast cancer management.”

https://www.sciencedirect.com/science/article/abs/pii/S0925443926000256?via%3Dihub


Cannabinoids and skin cancer: Mechanistic insights, therapeutic potential, and translational perspectives

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“Skin cancer represents a significant global healthcare challenge, with rising incidence and persistent gaps in effective long-term management.

Recent evidence has identified the endocannabinoid system as an emerging therapeutic target offering novel pharmacological approaches for the prevention and treatment of various skin cancers.

Cannabinoids, through modulation of the endocannabinoid system, have demonstrated antitumor activity by inhibiting tumor proliferation, angiogenesis, invasion, and metastasis and by inducing apoptosis and autophagy in malignant cells.

This review synthesizes the most recent preclinical evidence on phytocannabinoids, endocannabinoids, and synthetic cannabinoids in melanoma and non-melanoma skin cancers, delineating receptor-dependent and receptor-independent mechanisms. Additionally, emerging cannabinoid-based delivery strategies, particularly cannabidiol formulations designed to enhance skin penetration and therapeutic efficacy, are critically examined. Despite encouraging preclinical findings, clinical translation remains limited by scarce skin-cancer-specific trials, variability in cannabinoid preparations, and uncertainties around dosing and safety. Consequently, robust mechanistic studies and well-designed clinical trials are required to validate cannabinoids’ therapeutic potential and guide their integration into future skin cancer treatment paradigms.”

https://pubmed.ncbi.nlm.nih.gov/41621140

“Cannabinoids show anticancer effects in melanoma and non-melanoma skin cancers.”

https://www.sciencedirect.com/science/article/pii/S0014480026000067?via%3Dihub


Cytotoxicity of Cannabinoids in Combination with Traditional Lymphoma Chemotherapeutic Drugs Against Non-Hodgkin’s Lymphoma

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“Background: Cannabinoids (CBs) are FDA-approved for mitigating chemotherapy-induced side effects such as pain, nausea, and loss of appetite. Beyond palliative care, CBs exhibit anti-tumor properties in various cancers, including non-Hodgkin’s lymphoma (NHL). Previously, we demonstrated the cytotoxic effect of endogenous and exogenous cannabinoids on human and canine B- and T-cell-type NHL cell lines. The purpose of this study was to establish the cytotoxic effect of cannabinoids in combination with the components of CHOP and lomustine. This traditional NHL chemotherapy regimen comprises cyclophosphamide, doxorubicin, vincristine, and prednisolone. 

Methods: In this study, we studied three cannabinoids, one from each of the three major categories of cannabinoids (endocannabinoid AEA, phytocannabinoid CBD, and synthetic cannabinoid WIN-55 212 22). Each cannabinoid was selected based on potency, as determined in our previous experiments. For the combination, we used five NHL chemotherapy drugs. We analyzed the cytotoxicity of each drug alone and in combinations using canine malignant B-type NHL cell line 1771 and a colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide) cell proliferation assay and combination index (CI) based on the Chou-Talalay method. 

Results: Our results demonstrate that the cytotoxic effects of all traditional NHL chemotherapy drugs are synergistically enhanced (interaction with CI < 1) by each of the three cannabinoids at sub-IC50 concentrations. 

Conclusions: This work provides a proof of concept for using cannabinoids and traditional NHL drugs in combination to reduce the dose, and thereby potentially reducing the toxicity, of chemotherapeutic drugs and increasing the survival benefit in lymphoma clinical translation studies, offering a significant advancement in cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/41595541

https://www.mdpi.com/2227-9059/14/1/3