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

Effects of Cannabidiol on TAFAZZIN-Deficient B-Lymphoblastoid Cells

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“Barth Syndrome (BTHS) is a debilitating X-linked genetic disorder caused by mutations in the gene encoding TAFAZZIN, an enzyme responsible for the remodeling of cardiolipin. While cyclic neutropenia is a well-recognized immunological feature of this disease, emerging evidence suggests that lymphopenia may also occur.

The objective of this study was to examine the effects of cannabidiol (CBD) on growth, cardiolipin content, and mitochondrial abnormalities in BTHS patient-derived B-lymphoblastoid cells.

CBD (1 μM) restored the growth of BTHS B-lymphoblastoids to healthy control levels, but did not alter cell cycle distribution or sub-G1 cell populations, which surprisingly also did not differ from healthy control B-lymphoblastoids. CBD treatment also fully restored the total cellular cardiolipin concentration and reversed the elevation in monolysocardiolipin/cardiolipin ratio in BTHS B-lymphoblastoids to healthy cell levels, but did not restore the cardiolipin fatty acyl composition.

Assessment of mitochondrial markers suggested that increased cardiolipin did not result from increased mitochondrial content. This improvement in cardiolipin concentration was associated with a significant increase in the maximal coupled state III respiration of BTHS B-lymphoblastoids, with all five tested BTHS donors exhibiting increased mitochondrial membrane potential following CBD treatment. CBD fully reversed the deficit in succinate dehydrogenase subunit A in BTHS cells, and partially reversed deficits in cytochrome c oxidase subunits I and IV, and partially restored supercomplex I/III2 levels, but did not rescue I/III2/IV levels.

This work suggested a potential role for CBD as a therapeutic in BTHS B-lymphopenia that merits further investigation.”

https://pubmed.ncbi.nlm.nih.gov/41823370

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202503384R

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

Efficacy of Exogenous Cannabinoids in Pre-Clinical Models of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

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“Background: Exogenous cannabinoids are considered promising therapeutic candidates for inflammatory bowel disease (IBD). However, robust pre-clinical evidence supporting its efficacy remains limited. This systematic review and meta-analysis aimed to evaluate the therapeutic effects of exogenous cannabinoids in animal models of IBD.

Methods: Controlled experimental studies involving animal models of IBD that evaluated the effects of exogenous cannabinoids compared to untreated models were included. Four databases (PubMed, Embase, Web of Science, and the Cochrane Library) were searched up to August 26, 2025. Two independent reviewers conducted study selection, data extraction, and the risk-of-bias assessment. The risk-of-bias assessment was performed using the Systematic Review Center for Laboratory Animal Experimentation tool. Meta-analyses were performed using standardized mean differences (SMDs) and random-effects models. The study was registered in INPLASY (INPLASY202540009).

Results: Twenty-seven pre-clinical studies involving 408 animals were included. Compared with controls, exogenous cannabinoids significantly reduced disease activity index (SMD = -3.43; 95% confidence interval [CI]: -4.98 to -1.89; I2 = 83%) and histopathological score (SMD = -4.46; 95% CI: -6.37 to -2.54; I2 = 84%). It also decreased levels of myeloperoxidase (MPO), TNF-α, IL-6, and IL-1β. However, substantial heterogeneity was noted across several outcomes.

Interpretation: Exogenous cannabinoids show beneficial effects in pre-clinical IBD models, likely through anti-inflammatory, antioxidant, and barrier-enhancing mechanisms. These findings provide a supportive foundation for future translational research. Nevertheless, the overall certainty of the evidence is limited by unclear randomization, lack of blinding, high heterogeneity, and small sample sizes. Although some clinical trials have already begun exploring its therapeutic potential, further rigorous and standardized animal studies are needed to clarify mechanisms, optimize dosing, and reinforce the translational pathway.”

https://pubmed.ncbi.nlm.nih.gov/41804536

Therapeutic relevance of an EU-GMP certified Cannabis sativa L. strain in a dual in vivo model of cognitive impairment and chronic neuropathic pain

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“Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and frequently co-occurs with chronic pain. Worldwide, over 55 million people are affected by AD, with nearly half experiencing persistent pain. Chronic pain has been linked to accelerated memory deterioration and an increased risk of dementia, but the interplay between these conditions remains poorly understood. Existing therapies for AD and chronic pain are limited in efficacy, highlighting the need for interventions targeting multiple pathological pathways. The endocannabinoid system, which is altered in both AD and chronic pain, represents a potential therapeutic target, though its role in AD patients with comorbid pain remains unexplored.

Methods: The study evaluated the effects of an EU-GMP certified Cannabis sativa L. strain (5 mg/kg, Cannabixir® Medium Flos) on neurobiological alterations in a rat model designed to explore mechanistic interactions between scopolamine-induced transient cognitive impairment and chronic neuropathic pain induced by unilateral sciatic nerve ligation. Treatment outcomes were assessed through nociceptive tests, clinical monitoring and tissue analyses to examine cognitive and pain-related effects.

Results: Cannabixir® Medium Flos induced robust, time-dependent analgesia in thermal nociceptive tests, with the combination of the Cannabis sativa L. strain, donepezil and tramadol producing significantly longer response latencies than tramadol alone. Mechanical sensitivity was minimally affected across treatments. Immunohistochemical analyses revealed that Cannabixir® Medium Flos, either alone or in combination with donepezil or tramadol, produced the most pronounced neuroprotective effects, reducing astrocytic (GFAP) and microglial (Iba1) activation, lowering Caspase-3 and IL-6 expression, and preserving both hippocampal neuronal integrity as well as peripheral nerve structure.

Conclusion: These findings indicate that Cannabixir® Medium Flos, particularly when combined with donepezil and tramadol, provides superior analgesic and neuroprotective effects compared to tramadol alone. Its multi-target action – alleviating thermal nociception, reducing neuroinflammation, limiting apoptosis and preserving neuronal and peripheral nerve integrity-supports its potential as an adjunct therapy in managing dementia with comorbid chronic neuropathic pain. Future studies should explore the molecular mechanisms underlying these effects and assess long-term safety and efficacy across diverse models of neurodegeneration and chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/41800101

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1761426/full

Therapeutic Potential of Cannabinoids in Attenuating Amiodarone-Induced Pulmonary Fibrosis: An in vivo Experimental Study in Wistar Rats

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“Introduction: Amiodarone (AMIO) is one of the most prescribed antiarrhythmic medications and is commonly used to treat atrial and ventricular fibrillations. A notable adverse effect of AMIO is pulmonary fibrosis. Cannabinoid (O-2545) has been shown to exert antioxidant, anti-inflammatory, and antifibrotic effects in both in vivo and in vitro experimental models. The present study aimed to investigate whether cannabinoid (O-2545) may attenuate amiodarone-induced pulmonary fibrosis in male Wistar rats.

Methods: A regimen of 50 mg/kg AMIO was administered via oral gavage daily for 10 consecutive days to induce acute pulmonary fibrosis. The experiment included 24 Wistar rats assigned to four groups. The control group received daily subcutaneous injections of normal saline for the same time period. The AMIO group received a daily oral gavage of AMIO (50 mg/kg) for 10 days. Concurrently, the O-2545 group received daily oral doses of cannabinoid. The combined treatment group received both AMIO and cannabinoid orally each day for 10 days.

Results: High-dose AMIO (50 mg/kg) administration resulted in a significant elevation of oxidative stress, followed by a decrease in antioxidant function, an increase in inflammatory cytokines, fibrosis markers, and apoptosis. Pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and adenosine (Adens), apoptotic markers tumor protein p53 (p53) and caspase 3 protein (caspase-3), oxidative stress malondialdehyde (MDA), fibrosis indicator hydroxyproline (HYDROX), and histone deacetylase (HDAC) activity, accompanied by a marked reduction in the antioxidant glutathione (GSH), compared to the control group. Histopathological examination of pulmonary tissues revealed that O-2545 significantly mitigated AMIO-induced pulmonary fibrosis.

In conclusion, the results showed that cannabinoid (O-2545) may offer significant therapeutic potential in mitigating pulmonary toxicity induced by AMIO in rats.

Purpose: This study investigates the possible protective therapeutic effects of (O-2545) on AMIO-induced pulmonary fibrosis in Wistar rats.”

https://pubmed.ncbi.nlm.nih.gov/41804454

https://www.dovepress.com/therapeutic-potential-of-cannabinoids-in-attenuating-amiodarone-induce-peer-reviewed-fulltext-article-DDDT

Peripheral Cannabinoid Receptor Activation Attenuates Frostbite-Induced Chronic Pain via Modulation of TRP Channels, Neuroinflammation, and Autophagy

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“Frostbite injury is a debilitating cold injury encountered in extreme high-altitude and subzero environments, frequently resulting in persistent chronic pain even after tissue healing. Using our previously validated frostbite-induced chronic pain model, we further investigated the contribution of neuroimmune, excitatory mechanisms and evaluated the therapeutic efficacy of peripheral cannabinoid receptor activation.

Frostbite produced significant mechanical allodynia, mechanical hyperalgesia, and cold hypersensitivity, along with increased spontaneous nocifensive behaviors.

Local peripheral administration of CB13, a peripherally acting CB1/CB2 receptor dual agonist, dose-dependently attenuated both mechanical and cold allodynia without impairing locomotor activity, indicating a lack of central nervous system side effects.

At the molecular level, frostbite induced marked peripheral and spinal sensitization, demonstrated by elevated expression of TRPV1, TRPA1, TRPV4, and TRPM8 channels, increased levels of pro-inflammatory cytokines, and enhanced c-Fos expression as an indicator of heightened neuronal activation in pain-relevant regions. These alterations were accompanied by pronounced microglial activation and upregulation of the NLRP3 inflammasome.

CB13 treatment significantly reversed these pathological changes and concurrently restored Beclin-1-associated autophagy signaling, suggesting engagement of both neuroimmune resolution and intracellular homeostasis pathways. Notably, frostbite injury was associated with marked oxidative and nitrosative stress in the sciatic nerve, as evidenced by reduced glutathione depletion and elevated lipid peroxidation and nitrite levels, which were significantly normalized by CB13 treatment.

Collectively, these findings demonstrate that peripheral cannabinoid receptor activation effectively inhibit frostbite induced chronic pain through modulation of nociceptive, neuroinflammatory, redox, and cellular stress pathways.

This work highlights peripherally selective cannabinoid receptor agonists as promising, safer therapeutic strategies for chronic pain associated with cold injuries.”

https://pubmed.ncbi.nlm.nih.gov/41802611

“This study demonstrates that peripheral cannabinoid receptor activation via CB13 effectively alleviates frostbite-induced chronic pain by targeting multiple pathological mechanisms, including nociceptor hyperexcitability, spinal neuronal activation, neuroinflammation, inflammasome signaling, oxidative stress, and impaired autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584926001565?via%3Dihub