Category Archives: Cancer

Cannabigerol Induces Endoplasmic Reticulum Stress-Mediated Apoptosis and Ferroptosis via the IRE1α-XBP1 Axis in Human Pancreatic Cancer Cells

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“Cannabigerol (CBG), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention owing to its antibiotic, anti-inflammatory, and anticancer properties. However, its therapeutic potential in pancreatic cancer remains unknown.

In this study, we demonstrated for the first time that CBG exerts a potent antiproliferative effect on human pancreatic cancer cells by inducing cell cycle arrest in the G1 phase and promoting programmed cell death.

Transcriptomic profiling revealed that CBG significantly modulates the gene networks involved in apoptosis and ferroptosis. Consistent with these findings, CBG treatment upregulated apoptosis-associated proteins, such as cleaved caspase-3, caspase-9, and PARP1, and increased the proportion of apoptotic cells. CBG triggered robust activation of the unfolded protein response (UPR), with a marked increase in the transcriptional levels of endoplasmic reticulum (ER) stress-related genes.

Mechanistically, CBG activated the IRE1α-XBP1 axis, a key branch of the UPR, as evidenced by enhanced XBP1 mRNA splicing. Inhibition of IRE1α by the small-molecule inhibitor 4μ8C substantially mitigated CBG-induced cytotoxicity, emphasizing the central role of ER stress pathways in the mechanism of CBG’s action. Moreover, CBG modulated the expression of ferroptosis-related genes and proteins, such as DDIT3, NFE2L2, and HMOX1, and their respective protein products, CHOP, NRF2, and HO-1.

These findings reveal a novel mechanism by which CBG concurrently induces apoptosis and ferroptosis via ER stress-driven activation of the IRE1α pathway, supporting its potential as a therapeutic agent targeting ER stress-related vulnerabilities in pancreatic cancer.”

https://pubmed.ncbi.nlm.nih.gov/41871732

“In conclusion, this study provides compelling evidence that CBG induces ER stress-mediated apoptosis and ferroptosis in pancreatic cancer cells via IRE1α–CHOP axis activation. These findings enhance our understanding of the anticancer mechanisms of CBG treatment and suggest its potential as a multitargeted therapeutic agent.”

https://www.sciencedirect.com/science/article/pii/S089158492600242X?via%3Dihub

Role of Oncoviruses in Cancer Progression and Emerging Phytochemical-Based Therapies from Medicinal Plants

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“Oncoviruses continues to be an unattended cause of the global cancer load as they cause about 12-15 % of human malignancies in the world. The oncogenic infections that become persistent, such as Human Papillomavirus (HPV), Epstein-Barr Virus (EBV), Hepatitis B and C viruses (HBV, HCV), Human T cell Leukemia Virus-1 (HTLV-1), and Kaposi Sarcoma-associated Herpesvirus (KSHV), are associated with malignant transformation by continuous destabilization of host cell cycle regulation, immune surveillance, and metabolic homeostasis. These viruses abuse critical oncogenic signaling networks like PI3K/AKT/mTOR, NF -KB, JAK/STAT, MAPK, Wnt/β-catenin, and p53-dependent networks, hence, facilitating unchecked proliferation, chronic inflammation, genomic instability, and tumor progression.

Although there have been improvements in the traditional forms of treatment, such as chemotherapy, radiotherapy, antiviral agents, immunotherapy, and gene-based treatments, yet clinical outcomes are still hampered by drug resistance, viral latency, systemic toxicity, and inaccessibility, and other severe side effects especially in low- and middle-income nations. Hence, there is a dire need to introduce new medicinal plant-based therapeutic approaches against oncovirus.

This review analyses the molecular pathways of viral oncogenesis critically and discusses the clinical translation and a promising future potential of phytochemicals derived from medicinal plants like Phyllanthus emblica, Datura stramonium, Cannabis sativa, Andrographis paniculata, Aegle marmelos, Calotropis procera, and Prosopis cineraria proven to have bioactive compounds functioning as antivirals, immune-modulator, pro-apoptotic, and cell cycle regulatory effects in the preclinical models along with multi-targets.”

https://pubmed.ncbi.nlm.nih.gov/41824191

https://link.springer.com/article/10.1007/s12033-026-01561-6

Hyaluronic Acid-Functionalized Liposomes for Co-delivery of 5-Fluorouracil and Cannabidiol Against Colorectal Cancer

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“Purpose: Colorectal cancer (CRC) is a formidable global health challenge, ranking as the third most prevalent cancer. Conventional treatments like surgery, radiation, and chemotherapy are limited by adverse effects, driving the search for more effective alternatives.

Methods: This study investigates the synergistic potential of co-delivering 5-fluorouracil (5-FU) and cannabidiol (CBD) using hyaluronic acid (HA)-decorated liposomes. While 5-FU is a cornerstone of CRC treatment, CBD offers promise as an anti-tumor agent. The HA-decorated liposomes enable potential targeted drug delivery to CD44 receptors, which are overexpressed in CRC, while minimizing systemic toxicity by reducing the concentrations of anticancer drugs required.

Results: The liposomal formulation displays optimal physicochemical properties (a sub100nm size and an appropriate negative zeta potential) and acceptable encapsulation and loading efficiencies, ensuring effective drug release. In vitro studies demonstrate that the targeted liposomes have superior anticancer effects, inducing apoptosis (up to 59.1%), cell cycle arrest in the Sub-G1 and G0-G1 phases, reduction of cell viability to 6.98% in human colorectal adenocarcinoma (HT-29) cells, induction of oxidative stress, and inhibition of colony formation. Additionally, HepG2 (non-CD44-expressing) cells were used as a control to evaluate CD44-targeting efficiency. Gene expression analysis by real-time PCR indicates modulation of key genes associated with cell cycle progression and apoptosis.

Conclusion: This multifaceted approach presents a promising strategy for CRC therapy, but requires additional optimization and rigorous in vivo investigations to facilitate successful clinical translation. In particular, optimization of drug-release kinetics and thorough in vivo validation are essential to advance this platform toward clinical application.”

https://pubmed.ncbi.nlm.nih.gov/41835056

https://apb.tbzmed.ac.ir/Article/apb-43401

Exosomal cannabidiol: A promising candidate for targeted oral delivery against breast cancer

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“Breast cancer (BCa) remains a leading cause of cancer-related deaths in women worldwide. Triple-negative BCa (TNBC) is highly metastatic with treatment limited by off-target toxicity.

Cannabidiol (CBD) has anti-cancer and anti-inflammatory activity in BCa.

This study addresses the poor oral bioavailability of CBD by utilizing exosomes (Exo) as a drug delivery system.

CBD was loaded onto non-functionalized exosomes and folic acid-functionalized exosomes (FA-Exo), achieving an average CBD drug load of ∼20%. The FA-ExoCBD averaged 136 ± 2.9 nm in size. TNBC cell lines MDA-MB-231 and taxol-resistant MDA-MB-231TR were sensitive to growth inhibition by CBD than estrogen receptor positive (ER+) MCF-7 and its taxol-resistant derivative MCF-7TR. Exosomal formulations (ExoCBD and FA-ExoCBD) demonstrated time-dependent CBD release under physiologically relevant simulated gastric and intestinal conditions and withstand acidic conditions, retained canonical exosomal markers (CD81 and Alix) as well as physical parameters of exosomes including size, PDI and zeta potential.

CBD downregulated key anti-apoptotic and anti-inflammatory markers.

Oral FA-ExoCBD showed enhanced tumor targeting, tumor retention and inhibition of orthotopic MDA-MB-231-tumor growth in NOD Scid mice than ExoCBD or free CBD. RNA-Seq analysis of tumor tissues revealed that both CBD and FA-ExoCBD treatments modulated over 1000 genes, with FA-ExoCBD significantly downregulating IL13RA2 (associated with lung metastasis) and tumor biomarkers TRPM2 and SAMHD1, while upregulating tumor suppressors PRDM1, PCDHGB2, and ICAM1.

These findings highlight the potential of FA-ExoCBD to enhance CBD’s anticancer efficacy through targeted gene modulation. Overall, FA-ExoCBD improves CBD’s therapeutic profile by enhancing efficacy, tumor selectivity, improved bioavailability and anticancer efficacy.”

https://pubmed.ncbi.nlm.nih.gov/41812824

https://www.sciencedirect.com/science/article/abs/pii/S0304383526001795?via%3Dihub


Potential of Using Cannabidiol as a Therapeutic Molecule Against Various Cell Signaling Molecules Involved in Breast Cancer Complications: A Bioinformatics Approach

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“Background: Breast cancer progression involves key processes such as uncontrolled cell proliferation, resistance to apoptosis, metastasis, and angiogenesis. Cannabidiol (CBD), a non-psy-choactive compound from Cannabis sativa, has shown promise for its anti-cancer properties. This study aimed to explore the interaction of CBD with proteins involved in these processes.

Methods: Molecular docking was performed to assess the binding affinity of CBD to four critical proteins: CDK6 (cell cycle regulator), BCL2 (anti-apoptotic protein), MMP2 (invasion-related en-zyme), and VEGFR2 (angiogenesis-related receptor). Known inhibitors, palbociclib, ABT-199, doxycycline, and axitinib, were used as reference compounds for comparison.

Results: Cannabidiol exhibited strong binding affinities for CDK6, BCL2, MMP2, and VEGFR2. The docking scores were comparable to those of the respective standard inhibitors, suggesting effec-tive interactions with the active sites of the target proteins.

Discussion: These findings suggest that CBD may simultaneously target multiple cancer-related pathways, offering a potential multi-target therapeutic approach for breast cancer. Its comparable efficacy to standard inhibitors, combined with a favorable safety profile, supports its potential for further development. However, experimental validation through in vitro and in vivo studies is neces-sary to confirm its therapeutic effectiveness.

Conclusion: CBD demonstrates promising multi-target activity against critical signaling molecules in breast cancer and may serve as a safer, natural therapeutic candidate. Further preclinical and clin-ical investigations are warranted.”

https://pubmed.ncbi.nlm.nih.gov/41830580

https://www.eurekaselect.com/article/153254

Quantitative analysis of Cannabinoid Therapy in Prostate Cancer: Integrating Biomarkers, Imaging and Patient Outcomes

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“Cannabinoids are increasingly used by cancer patients for symptom relief, yet clinical evidence on their effect in prostate cancer remains limited. This study evaluated the association between cannabinoid therapy and disease activity, pain, and quality of life in men with prostate cancer.

The objectives were to assess the influence of cannabinoids on PSA levels, metabolic activity, tumour size via PET/CT scans, and patient-reported outcomes including pain levels and quality of life.

Methods: Ninety men with confirmed prostate cancer were prospectively followed in three groups: chemotherapy-only, cannabis-only, and combined chemotherapy + cannabis. PSA, PET/CT findings, and patient-reported outcomes (BPI, EQ-5D) were assessed at baseline, 3 months, and 6 months. Longitudinal changes were analysed using linear mixed-effects regression with group × time interactions, and between-group differences were tested with ANOVA. PET/CT categorical outcomes were evaluated using multinomial logistic regression to generate adjusted odds ratios

Results: Significant temporal differences in PSA levels were detected among groups (p < 0.001); both cannabis-containing regimens showed faster PSA decline, but final values were comparable across treatments. PET/CT analyses indicated a higher likelihood of remission or tumour reduction in the combined group (p = 0.013).

Cannabis use, alone or combined was associated with greater reductions in pain and improved emotional well-being compared with chemotherapy alone, while improvements in self-care and usual-activity scores were also observed.

Conclusion: Cannabinoid therapy, whether used independently or alongside chemotherapy, was associated with improved pain control and some indicators of tumour response, without evidence of harm. The findings warrant cautious interpretation and support further randomized studies to clarify cannabinoids’ adjunctive role in prostate cancer management.”

https://karger.com/mca/article/doi/10.1159/000550792/946276/Quantitative-analysis-of-Cannabinoid-Therapy-in

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