“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.”
“Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed.
The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response.
Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models.
The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC.
In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems.”
“The endocannabinoid system (ECS) plays a crucial role in the development and functioning of several biological systems. Classically, the endocannabinoid system comprises receptors, endogenous ligands, and enzymes that synthesize, transport, and degrade such ligands. ECS regulates many biological processes, both in normal conditions like brain function, neurotransmitter release, sleep regulation, appetite, movement, and coordination, as well as pathological states such as neurodegenerative disorders, headaches, chronic pain, anxiety, depression, and cancer, among others.
Accordingly, pharmacological modulation of the endocannabinoid system may be a potential target for preventing disease progression or enhancing symptom relief in multiple conditions, including cancer “
“Dysregulation of voltage-gated sodium channels causes the development of several diseases. CBD is a non-selective Nav1.1–1.7 sodium channel inhibitor and is effective in the treatment of epilepsy.”
“Exploiting the cannabidiol-ion channel-transporters association represents an extraordinary opportunity for liver cancer prevention and therapy, which may help to reduce the high mortality from this malignancy and to involve sociocultural, public health, regulatory, and economic systems.”
“Taken together, preclinical, epidemiological, and clinical data converge to support CBD as a promising candidate for the prevention and management of liver diseases and HCC, with potential implications for sociocultural, public health, and economic systems.”
“Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with a grim prognosis. Current treatment options for advanced HCC are limited, and a large proportion of patients is not amenable to any form of treatment, with best supportive care as the only remaining option.
Meanwhile, the use of cannabis-derived products is rising in oncological patients who are seeking symptom relief. Cannabinoids, similar to endogenous endocannabinoids, have shown promise in recent preclinical cancer research due to their ability to interact with various signaling pathways and molecular mechanisms of interest.
Case presentation
In this report, we present two patients (A aged 82 and B 77, respectively) with advanced HCC with a high tumor burden who demonstrated durable and complete regression after use of cannabis oil (A 10% delta-9-tetrahydrocannabinol (THC) and 5% cannabidiol (CBD), two droplets sublingually three times daily and B 15% THC and 2% CBD, 5 droplets sublingually two times daily) for symptom relief. The observations in this report build on previous (pre)clinical research highlighting the potential anti-tumor qualities of cannabinoids and stress the need for clinical trials investigating the anti-tumor effects of cannabinoids in cancer patients.
Conclusion
Based on the two cases presented here, we call for further research into the potential beneficial effect of cannabinoids in patients with advanced HCC.”
“The authors present two cases of durable and complete remission in two patients with advanced hepatocellular carcinoma using cannabinoids, thus stressing the call for further research into the anti-tumor effects of cannabinoids in this patient population with limited therapeutic options. These findings are hypothesis-generating and underscore the urgent need for controlled clinical trials.”
“Cannabis sativa is one of the most extensively researched plant species that holds promising therapeutic and ethnomedicinal significance.
Various parts of the species including fan leaves, flowers and trichomes are well documented for their richness in cannabidiol (CBD) and tetrahydrocannabidiol (THC) contents. However, an overlooked part of C. sativa, the sugar leaves, which are wasted during harvesting has plethora of CBD and THC and yet to investigated.
In this study we investigated the ethanol extract of sugar leaves of C. sativa (CSLE) for chemical composition through UHPLC-Q-TOF-MS analysis and pharmacological potential by using various in vitro antioxidant, antidiabetic, nitric oxide inhibition and anticancer studies. Furthermore, in silicomolecular docking analysis was performed for 10 selected compounds against α-glucosidase and α-amylase.
The UHPLC-Q-TOF-MS profiling of CSLE revealed the tentative identification of 37 compounds including CBD, THC, terpenes and flavonoids. The cytotoxicity studies presented highest activity against breast cancer cell lines (MDA-MB-231, IC50= 18.12 ± 1.13 µg/mL) followed by lung, liver and colorectal cancer cell lines.
Similarly, CSLE showed significant antidiabetic activity by inhibiting α-glucosidase (IC50= 3.13 ± 2.78 µg/mL) and α-amylase. The in vitro antioxidant assays gave highest activity in ABTS followed by DPPH method as well as potentially inhibited nitric oxide (NO) formation. The computational analysis revealed good docking interaction of CBD, THC, selected terpene and flavonoids against α-glucosidase and α-amylase.
Overall, the findings present the sugar leaves of C. sativa as the undisputed rich source of CBD, THC, terpenes and flavonoids with multifaceted therapeutic potential in diabetes, inflammation and different types of cancers. However, there is need of further investigations on toxicity profile and in-depth pharmacological evaluation through in vivo disease bearing animal models.”
“The research titled “UHPLC-Q-TOF-MS profiling and multifaceted antioxidant, antihyperglycemic and anticancer potential of Cannabis sativa sugar leaves: An unexplored source of cannabidiol, terpenes and polyphenols” identifies sugar leaves of Cannabis sativa as a potential source for multiple therapeutic compounds, including cannabidiol, terpenes, and polyphenols. Through UHPLC-Q-TOF-MS analysis, the study found that these sugar leaf extracts exhibit antioxidant, antihyperglycemic (anti-diabetic), and anticancer activities against various cancer cell lines. The specific compounds present in the sugar leaves, when combined with other plant compounds like terpenes and flavonoids, demonstrate a phenomenon known as the entourage effect, which could enhance their therapeutic potential.”
“Cancer is the second leading cause of global mortality after cardiovascular diseases, with breast, lung, colon, and prostate cancers being the most common. WHO projects around 30 million new cancer cases worldwide by 2045, with breast cancer being the most common in women and lung cancer in men.
Metastasis is responsible for nearly 90% of cancer-related deaths. Breast and lung cancers tend to metastasize to the bones, lymph nodes, lungs, liver, and brain. Lungs remains one of the most common organs to which various forms of cancer metastasize.
An important factor in metastasis is NETosis – it can initially help to eliminate cancer cells, but it can also promote metastasis. Phytocannabinoids, compounds derived from Cannabis sativa, and the endocannabinoid system (ECS) offer promising therapeutic potential to inhibit NETosis and consequently cancer development and metastasis.
Although the precise effects of phytocannabinoids on neutrophil functions and NETosis are not fully understood and require further research in the context of cancer, preliminary studies suggest their potential to inhibit NET release in various disease models.
This review consolidates current knowledge and provides new insights into how phytocannabinoids and the ECS may serve as effective therapeutic tools to limit cancer metastasis.”
“Research indicates that metastatic progression is responsible for most deaths caused by breast cancer, with metastatic processes accounting for nearly 90% of cancer-related mortality.”
“Phytocannabinoids, together with the endocannabinoid system (ECS), represent a highly promising therapeutic avenue for attenuating neutrophil effector functions, particularly the process of NETosis.
We believe that these compounds have significant potential as agents capable of effectively inhibiting metastatic progression.
Phytocannabinoids, derived primarily from the Cannabis sativa plant, are a group of organic compounds that interact with the endocannabinoid system (ECS) in the human body.”
“Both phytocannabinoids and the endocannabinoid system (ECS) show significant therapeutic potential in cancer treatment. Research indicates that these agents affect the proliferation, apoptosis, migration, and invasiveness of cancer cells. In addition, they modulate the tumor microenvironment, particularly the cells of the immune system.”
“Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality with limited treatment options. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown anticancer properties.
This review analyzes CBD’s therapeutic potential in HCC, focusing on mechanisms, preclinical/clinical findings, and integration into treatment strategies. A systematic search (PubMed, Scopus, Web of Science, Google Scholar) up to March 2025 identified 16 relevant studies (in vitro, in vivo, clinical).
CBD exerts antitumor effects via multiple pathways, including apoptosis, autophagy regulation, metastasis suppression, and tumor microenvironment modulation. CBD interacts with the endocannabinoid system (ECS), inhibits oncogenic signaling (PI3K/AKT/mTOR), and enhances chemotherapeutic efficacy (sorafenib, cabozantinib).
Studies show CBD induces pyroptosis via caspase-3/GSDME, and modulates autophagy by inhibiting the PI3K/Akt/mTOR pathway. It also sensitizes HCC cells to sorafenib and cabozantinib. Preclinical results are promising, but clinical studies are limited. Challenges like bioavailability and potential hepatotoxicity require investigation. Future research should optimize formulations, determine dosing, and conduct clinical trials to validate CBD’s efficacy/safety in HCC patients.
Validated CBD could offer an innovative HCC management option.”
“Overall, while preclinical findings strongly support the therapeutic potential of CBD in HCC, robust clinical trials are urgently needed to confirm its efficacy, safety, optimal dosing strategies, and long-term effects. If validated, CBD could represent an innovative and complementary approach in the management of hepatocellular carcinoma.”
“Methotrexate (MTX), a widely used chemotherapeutic agent, often induces hepatotoxicity, limiting its clinical utility.
Cannabidiol (CBD), derived from hemp, possesses antioxidant, anti-inflammatory, and antiapoptotic properties.
This study aims to investigate CBD’s protective effects against MTX-induced liver injury and elucidate the underlying mechanisms.
Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (20 mg/kg intraperitoneally [i.p.] once), MTX+CBD (20 mg/kg i.p. once + 5 mg/kg i.p. for seven days), and CBD (5 mg/kg, i.p. for seven days). Biochemical analyses of serum and liver tissues were performed to assess oxidative stress markers (total oxidant status, total antioxidant status, oxidative stress index), liver function tests (AST, ALT), and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase). Histopathological and immunohistochemical examinations were conducted to evaluate liver tissue damage and TNF-α expression. Genetic analyses were performed to measure the expression levels of SIRT-1, p53, Bcl-2, and Bax genes using RT-qPCR. MTX administration increased oxidative stress markers, liver enzymes, TNF-α, p53, and Bax levels while decreasing antioxidant defenses and SIRT-1 expression.
CBD administration reversed these alterations effectively.
CBD mitigated MTX-induced hepatotoxicity by reducing oxidative stress, inflammation, and apoptosis. It activates antioxidant defenses via SIRT-1 upregulation, suppresses inflammation by reducing TNF-α, and prevents apoptosis by modulating p53, Bcl-2, and Bax gene expressions.
These findings suggest CBD could be a promising therapeutic agent for chemotherapy-induced liver damage. Further research is warranted to explore additional pathways and broader molecular mechanisms.”
“This study involved the synthesis of a series of novel cannabidiol (CBD) aromatic ester derivatives, including CBD-8,12-diaromaticester derivatives (compounds 2a-2t) and CBD-8,12-diacetyl-21-aromaticester derivatives (compound 5a-5c).
The antiproliferative activities of these compounds against human liver cancer cell lines HePG2 and HeP3B as well as human pancreatic cancer cell lines ASPC-1 and BXPC-3 were evaluated in vitro using the CCK-8 assay.
The results indicated that compound 2f exhibited an IC50 value of 2.75 µM against HePG2, which is 5.32-fold higher than that of CBD. Additionally, compounds 2b and 5b demonstrated varying degrees of improved anticancer activity (IC50 5.95-9.21 µM) against HePG2.”
“Cannabidiol (CBD) has antioxidant and anti-inflammatory activities. However, the anti-tumor effect of CBD on hepatocellular carcinoma (HCC) remains unclear. Here, we investigated whether CBD displays anti-tumorigenic effects in HCC cells and whether it could reduce tumorigenesis and metastases in vivo.
First, this study treated HCC cells with different concentrations of CBD, followed by analyzing the changes in the proliferative, apoptotic, migratory and invasive abilities. The effects of CBD on the growth and metastasis of HCC cells in vivo were verified by tumorigenesis and metastasis assays. Subsequently, the target genes of CBD were predicted through the SwissTarget website and the genes differentially expressed in cells after CBD treatment were analyzed by microarray for intersection. The enrichment of the pathways after CBD treatment was analyzed by KEGG enrichment analysis, followed by western blot validation. Finally, rescue assays were used to validate the functions of genes as well as pathways in the growth and metastasis of HCC cells.
A significant weakening of the ability of HCC cells to grow and metastasize in vitro and in vivo was observed upon CBD treatment. Mechanistically, CBD reduced GRP55 expression in HCC cells, along with increased TP53 expression and blocked MAPK signaling activation. In CBD-treated cells, the anti-tumor of HCC cells was restored after overexpression of GRP55 or deletion of TP53. CBD inhibits the MAPK signaling activation and increases the TP53 expression by downregulating GRP55 in HCC cells, thereby suppressing the growth and metastasis of HCC cells.”
“Photodynamic therapy (PDT) and cannabidiol (CBD) have been explored for their potential in synergistic cancer treatment. In this study, we employed CBD oil as a lipid phase, encapsulated within AZB-I@Lec-T to create lipid-based nanoparticles. Here, CBD oil does two tasks: it acts as a pyroptosis agent to destroy liver cancer cells and as a lipid phase to dissolve the photosensitizer. It was expected that this system would offer synergistic therapy between CBD and PDT better than a single use of each treatment. With a series of in vitro experiments, the nanoparticles exhibited induced apoptosis in 68% of HepG2 cells treated with AZB-I@Lec-T@CBD and near-infrared (NIR)-light irradiation, reducing expression levels of antioxidant defense system genes. Furthermore, both components worked well in a submicromolar range when combined in our formulation. These results highlight the potential for amplifying primary cellular damage with the combination of PDT and CBD encapsulation, providing a promising therapeutic approach for liver cancer treatment guidelines.”
“CBD is one of the prospective therapeutic options in oncology that has been shown to reduce angiogenesis, cancer cell motility, adhesion, and invasion, as well as limit secondary metastatic cancer spread.”
“This study successfully demonstrated the potent cytotoxic synergy between photodynamic therapy (PDT) and cannabidiol (CBD) in cancer cells.
These findings underscore the potential for augmenting primary cellular damage using PDT and CBD coencapsulation, offering a promising avenue for future therapeutic strategies in cancer treatment protocols.”
