Category Archives: Cancer

Neolignans isolated from industrial hemp (Cannabis sativa L.) roots have cytotoxic effects on cancer cells

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“Background: The 2018 Farm Bill states that cultivars of Cannabis sativa L. (industrial hemp) are legal for industrial use if total tetrahydrocannabinol (THC) concentrations are less than 0.30%. Due to this legislation, hemp cultivars with low total THC have found a wide range of uses, from animal feed to paper production. Although cannabinoids are the most widely studied compounds in hemp, hemp produces numerous other compound classes as well, and these phytochemicals may have uses in the functional food and pharmaceutical industry.

Methods: Initial liquid chromatography profiling of hemp root samples revealed a group of uncharacterized peaks, and these peaks were tentatively identified as neolignans by Oribitrap ID-X high resolution mass spectrometer. To further elucidate the structure of these neolignans, we used techniques in liquid-liquid extraction, as well as flash chromatography to isolate them in preparation for NMR analysis. We then tested their inhibitory concentration 50 (IC50) in a variety of cancer cell lines.

Results and discussion: Four neolignans were isolated from hemp roots and each differed in their molecular weight by 30 daltons. Two of the compounds were identified as dadahols A and B. We tested fractions of various purities containing neolignans against neuroblastoma cell lines CHLA15 and LAN5, hepatoblastoma cell line Hep3B, and Hodgkin’s lymphoma cell line L428. We found that semi-pure fractions containing dadahol A and/or dadahol B had the highest cytotoxic activity. We then tested pure dadahol A and dadahol B, and this revealed dadahol A exhibited the lowest IC50 values in all the cell lines.”

https://pubmed.ncbi.nlm.nih.gov/40818965/

“We report, for the first time, that dadahols, using the methodologies described herein, have antiproliferative effects. While our findings demonstrate the cytotoxic effects of hemp-derived compounds on multiple pediatric cancer cell lines, the underlying mechanisms driving these effects remain to be elucidated.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00316-5

The Role of the Endocannabinoid System in Oncology and the Potential Use of Cannabis Derivatives for Cancer Management in Companion Animals

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“The last decades of research have shown that the endocannabinoid system may be a promising therapeutic target for the pharmacological treatment of cancer in human medicine and possibly in veterinary medicine as well.

Compared with the original cells, the expression of gene encoding for receptors and enzymes belonging to the endocannabinoid system has been found to be altered in several tumor types; it has been hypothesized that this aberrant expression may be related to the course of the neoplasm as well as to the patient’s prognosis.

Several studies, conducted both in vitro and in vivo, suggest that both endo- and phytocannabinoids can modulate signaling pathways, controlling cell proliferation and survival. In the complex process of carcinogenesis, cannabinoids seem to intervene at different levels by stimulating cell death, inhibiting the processes of angiogenesis and metastasis, and regulating antitumor immunity.

Although the molecular mechanisms by which cannabinoids act are not always clear and defined, their synergistic activity with the most used antineoplastic drugs in clinical oncology is showing promising results, thus providing veterinary medicine with alternative therapeutic targets in disease control.

This review aims to summarize current knowledge on the potential role of the endocannabinoid system and exogenous cannabinoids in oncology, with specific reference to the molecular mechanisms by which cannabinoids may exert antitumor activity. Additionally, it explores the potential synergy between cannabinoids and conventional anticancer drugs and considers their application in veterinary oncology.”

https://pubmed.ncbi.nlm.nih.gov/40804975/

“Companion animals are more and more becoming considered family members, and their owners wish to offer them the same level of cure and care expected for a human being. The long life expectancy of dogs and cats is associated with new challenges: veterinary medicine must be prepared to diagnose and treat neoplastic pathology with the same high-standard procedures that are currently used in human medicine.

Chemotherapies aim to prolong as long as possible the life of companion animals affected by cancer, but several side effects can be experienced. Thus, an increasing interest in alternative and complementary treatments has arisen in the last years. Among a wide array, cannabinoids seem to be a promising tool to be included in therapeutic protocols since their administration could assist traditional chemotherapeutic agents, promoting a more successful antineoplastic effect, prolonging the prognosis, and contributing to patient well-being thanks to pain relief.

According to all the aforementioned factors, the present review aims to summarize how the endocannabinoid system and phytocannabinoids interact in the complex process of carcinogenesis, exploring current therapeutical applications and future perspectives in veterinary oncology.”

“From the above paragraphs, it can be concluded that cannabinoids show antitumor activity (decrease in tumor growth and invasiveness) in numerous cell lines and in various animal models of cancer, and that, although clinical studies conducted in human and animal patients are limited, the results obtained so far have demonstrated that cannabinoids appear to be safe and effective antineoplastic agents.

Moreover, most of the preclinical evidence currently available demonstrates that the greatest therapeutic potential of cannabinoids lies in their combination with existing chemotherapeutic drugs.

Interestingly, compared to conventional antineoplastic drugs, which have a plethora of side effects, cannabinoids (especially the non-psychoactive ones, such as CBD) have a broad safety margin. “

https://www.mdpi.com/2076-2615/15/15/2185

Cannabichromene: integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy

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“Cannabichromene (CBC: C21H3O2, M.W.: 314.46 g) is a non-psychotropic phytocannabinoid derived from Cannabis sativa (hemp), and its potential therapeutic properties have attracted increasing attention. Specifically, it has demonstrated strong anti-inflammatory effects in animal models of edema through non-CB receptor mechanisms; however, further pharmacological studies based on cancer models are required.

In this study, we investigated the molecular mechanisms underlying the anti-cancer activity of CBC in human pancreatic cancer cells.

Through mRNA-seq analysis, the expression levels of many genes involved in cell death pathways were upregulated or downregulated after CBC treatment, and these included ferroptosis-related genes, such as HMOX1. We further confirmed the functional validity of apoptosis and ferroptosis induction after CBC treatment using various molecular assays. In addition, CBC preferentially increased the expression of TRPV1 and CB2.

Accordingly, the effects on cell death were reversed after treatment with TRPV1 and CB2 inhibitors, suggesting that receptor expression is necessary for the induction of apoptotic cell death. Finally, we confirmed the consistent regulation of apoptosis, ferroptosis, and endocannabinoid receptors during tumor growth inhibition after CBC treatment using in vivo xenograft models.

Therefore, we propose that CBC exhibits pharmacological activity via the integrative modulation of multiple cell death pathways, which can be exploited for pancreatic cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/40790027/

“Cannabinoids extracted from Cannabis sativa exert their effects by binding to specific receptors that play a role in tissue development and homeostasis maintenance in the human body.”

“CBC treatment induces apoptotic cell death in pancreatic cancer cells”

“Our current study demonstrates that CBC modulates multiple forms of cell death by regulating the expression of proteins involved in both apoptotic and ferroptotic pathways. Although CBC-induced apoptosis was dependent on TRPV1 and CB2 receptors, the ferroptotic pathway appeared to be independent of these receptors.

Accordingly, we propose that CBC exerts its pharmacological effects through the integrative modulation of multiple cell death pathways, which could offer therapeutic benefits for pancreatic cancer treatment.

These results enhance our understanding of how CBC induces diverse cell death mechanisms via ECS receptors, not only in pancreatic cancer but also in other cancer models.

This study provides a promising foundation for the development of cannabinoid-based anti-cancer drugs, offering a new strategy for targeting various types of cancer through the modulation of apoptosis and ferroptosis.”

https://www.nature.com/articles/s41420-025-02674-8

Recent Advances in the Therapeutic Potential of Cannabinoids Against Gliomas: A Systematic Review (2022-2025)

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“Glioma is the most common and lethal primary brain tumor in adults, with glioblastoma (GBM) representing the most aggressive subtype, characterized by diffuse infiltration, resistance to therapy, and a poor prognosis. Despite standard treatments, survival remains only approximately 14 months.

Cannabinoids have been increasingly investigated for their therapeutic potential in gliomas, particularly GBM. Although multiple reviews on this field of research have been published, most are current only up to 2022. This systematic review aims to provide an updated summary of studies published between 2022 and 2025, capturing recent developments in anti-glioma mechanisms, combinational strategies, immune modulation, and novel therapeutic platforms.

Following PRISMA guidelines, PubMed, Scopus, ScienceDirect, and SpringerLink were searched for original English-language journal articles published between January 2022 and February 2025, using search terms related to cannabinoids and brain cancer. From 1031 records, 45 original research articles were included after removing duplicates, non-primary studies, and irrelevant topics. The studies were categorized into seven thematic domains based on content.

Recent studies have elaborated on the anti-cancer mechanisms of cannabinoids beyond endocannabinoid signaling via the CB1/CB2 receptor, including ferroptosis induction, mitochondrial dysfunction, integrated stress response activation, and epigenetic modulation. Synthetic cannabinoids and their analogs demonstrated enhanced blood-brain barrier penetration and cytotoxicity in glioma models.

Cannabinoids have been shown to modulate immune responses in glioma, influencing T cell infiltration, myeloid suppressor cell recruitment, and tumor-associated macrophage function. Novel formulation and delivery strategies have improved cannabinoid solubility, stability, and tumor targeting. Combination therapies, particularly cannabidiol with temozolomide or radiotherapy, exhibited additive or synergistic anti-tumor effects, although variability between glioma subtypes suggests the need for personalized approaches.

Although cannabinoid-based glioma research has expanded our understanding of the mechanisms, discrepancies between preclinical findings and clinical data highlight the need for rigorous clinical trials and mechanistic research before cannabinoid-based treatments can be reliably integrated into standard glioma care.”

https://pubmed.ncbi.nlm.nih.gov/40781861/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.70160

Cannabidiol Suppresses EMT in Pancreatic Cancer via Inhibition of MALAT1 lncRNA and PI3K/Akt/mTOR Signaling Pathway

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“Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive metastasis and poor response to chemotherapy, largely driven by epithelial-mesenchymal transition (EMT) and chemokine signaling.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown anticancer potential, yet its mechanisms in EMT regulation remain underexplored in PDAC.

In this study, we demonstrate that CBD significantly suppresses the expression of CXCR4/CXCR7 and matrix metalloproteinases (MMP-2/9), leading to reduced migration and invasion of MIA PaCa-2, PANC-1, and AsPC-1 cells. Moreover, CBD reversed CXCL12-induced EMT by downregulating mesenchymal markers and restoring epithelial markers. Mechanistically, CBD inhibited the expression of the long non-coding RNA MALAT1, a known EMT regulator, and antagonized its pro-invasive effects. Overexpression of MALAT1 activated the PI3K/Akt/mTOR pathway and enhanced EMT-related protein expression, all of which were effectively reversed by CBD. Furthermore, the combination of CBD and gemcitabine exhibited synergistic inhibition of MALAT1, EMT markers, and PI3K/Akt/mTOR signaling without inducing cytotoxicity, suggesting a therapeutic advantage.

Collectively, these findings reveal a novel mechanism through which CBD impedes PDAC metastasis and underscore its promise as a complementary agent in chemotherapy regimens.”

https://pubmed.ncbi.nlm.nih.gov/40767250/

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has garnered considerable interest in oncology for its anti-inflammatory, pro-apoptotic, and anti-metastatic properties.”

“CBD has garnered increasing interest in oncology due to its multifaceted anticancer properties.”

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/iub.70042

Transient CB2 receptor activation triggers irreversible luminal differentiation via chromatin remodeling in breast cancer

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bioRxiv

“Cellular plasticity enables cancer cells to escape therapy by adopting stem-like or alternate lineage states. Here, we identify a mechanism by which cannabinoid receptor 2 (CB2R) activation promotes irreversible lineage commitment in breast cancer. Using patient-derived and murine organoids, we show that brief, low-dose exposure to CB2R agonists—either phytogenic or synthetic—induces a basal-to-luminal transition, accompanied by reduced self-renewal, invasiveness, and tumor-initiating potential. These changes are retained under conditions that normally promote dedifferentiation, including fibroblast co-culture, immune pressure, and mechanical shear stress.

Mechanistically, CB2R engagement initiates a transient chromatin remodeling program, marked by early expression of pluripotency-associated genes followed by silencing and differentiation commitment. This epigenetically stabilized state renders tumor cells more responsive to tamoxifen and limits the emergence of resistant clones.

Our findings uncover a previously unrecognized role for CB2R in modulating cancer cell identity and suggest new opportunities to constrain tumor plasticity by directing differentiation through a drug-responsive pathway.”

https://www.biorxiv.org/content/10.1101/2025.07.29.667375v2

CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy

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“Tumor adaptability relies on the ability of cancer cells to dedifferentiate and acquire stem-like features, fueling therapeutic resistance and metastasis. Differentiation therapy aims to reprogram tumor cells into more mature, less aggressive states to counteract this plasticity.

Here, we identify cannabinoid receptor 2 (CB2R) as a novel therapeutic target that promotes sustained differentiation in breast cancer. Using tumor-derived organoids from both mouse models and patient biopsies, we show that brief, low-dose exposure to phytogenic or synthetic CB2R ligands induces a basal-to-luminal switch, suppresses stemness, and reduces invasiveness and self-renewal. These phenotypic changes are associated with decreased tumor initiation and aggressiveness in vivo .

Transcriptomic profiling reveals that CB2R activation initiates transient chromatin remodeling and epigenetic reprogramming, resulting in a stably differentiated state. Importantly, CB2R-driven differentiation sensitizes tumor cells to tamoxifen, enabling lower therapeutic doses with improved efficacy-supporting the principles of adaptive therapy aimed at long-term disease control.

Our findings position CB2R modulation as a promising non-cytotoxic strategy to restrict cancer plasticity and enhance the effectiveness of existing breast cancer treatments.”

https://pubmed.ncbi.nlm.nih.gov/40766353/

Treatment of malignant diseases with phytocannabinoids: promising observations in animal models and patients

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“Amazingly, almost 50 years after the first demonstration of anticancer effects of cannabinoids in vitro and in vivo, well-designed clinical trials that definitively prove tumour-inhibiting effects in man are still missing. Whereas a large number of preclinical studies exist that describe tumour-inhibiting effects of cannabinoids, alone or in combination, but also in the form of medical cannabis or natural extracts in vitro, the number of in vivo studies is still limited. Even more limited are well-documented experiences in man. Most animal studies and experience with cannabinoids in man concern brain tumours.

This review summarises the effects of phytocannabinoids in brain, breast, colorectal, head and neck, haematological, liver, lung, pancreatic, ovarian, prostate, and skin cancers in animal models and, if available, in patients.

The large majority of animal studies demonstrate tumour-inhibiting effects of cannabinoids, thus confirming in vitro data. Experiences in cancer patients are almost exclusively limited to individual case reports and case series without a control group. Many questions are currently unanswered such as the role of pure cannabinoids compared to combinations, cannabinoids as the eventual sole cancer therapy, optimal dosages, or duration of treatment. Pure cannabidiol (CBD) seems to be superior to pure delta-9-tetrahydrocannabinol (THC) in experimental settings. The role of medical cannabis or extracts is less clear as they vary in their phytochemical composition.

In conclusion, cannabis/cannabinoids may slow the progression of tumours. However, the hope that cannabinoids could eventually cure cancer as often spread in social media, is, at present, wishful thinking. Above all, well-designed clinical trials paired with long-term follow-up of cancer patients are needed.”

“Cytotoxic effects of cannabinoids have been known since the very first series of in vitro and animal experiments by Munson et al. in 1975, almost 50 years ago, performed at the request of the National Institute on Drug Abuse (US). Since then, an overwhelming number of preclinical experiments have demonstrated the potential benefit of cannabinoids for treating malignant diseases.”

“In conclusion, although the number of studies in various animal cancer models as well as articles on therapeutic experience with cannabinoids in cancer patients is still very limited, the large majority describes impressing tumour-inhibiting effects warranting further research.”

https://www.explorationpub.com/Journals/em/Article/1001182

Pilot Study of Cannabidiol for Treatment of Aromatase Inhibitor-Associated Musculoskeletal Symptoms in Breast Cancer

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“Introduction: Aromatase inhibitor (AI) therapy reduces breast cancer recurrence risk. However, some patients stop treatment early because of AI-associated musculoskeletal symptoms (AIMSS). AIMSS is due in part to systemic inflammation. Cannabidiol (CBD) has anti-nociceptive and anti-inflammatory properties, making it a potential treatment option for AIMSS.

Methods: Women with stage 0-3 hormone receptor-positive breast cancer experiencing AIMSS enrolled in this phase 2 clinical trial. Patients received CBD (Epidiolex), titrated over 4 weeks to 100 mg BID, for a total of 15 weeks. Patient-reported outcomes were collected serially. The primary endpoint was the number of patients with at least a 2-point reduction in worst pain from baseline to 15 weeks. Statistical analysis was completed using paired t-tests and linear mixed models.

Results: Of 39 eligible patients, 28 completed protocol-directed study treatment. Eleven discontinued treatment due to toxicity (n = 5) or per patient preference (n = 6). Seventeen of 39 patients met the primary endpoint (43.6%, 95% CI [28%, 60%]). Worst pain improved 0.13 per week of treatment (p < 0.001) for all patients; average improvement in worst pain was 1.95 points at the end of 15 weeks. Of the 28 patients who completed the study, average reduction in worst pain was 2.36 points (95% CI [-3.22, -1.49]) between baseline and Week 15.

Conclusion: Treatment with CBD was safe, tolerable, and associated with improvement in joint pain for a subset of patients. Additional studies are needed to further understand the impact of CBD on AIMSS and which patients are most likely to benefit from CBD treatment.”

https://pubmed.ncbi.nlm.nih.gov/40751295/

“Treatment with CBD was associated with an improvement in AIMSS for a subset of patients. Use of CBD was safe and tolerable for women with hormone receptor-positive breast cancer.”

https://onlinelibrary.wiley.com/doi/10.1002/cam4.71117

Cannabidiol (CBD) and Colorectal Tumorigenesis: Potential Dual Modulatory Roles via the Serotonergic Pathway

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“The 2018 Farm Bill legalized hemp-derived cannabidiol (CBD) products containing less than 0.3% tetrahydrocannabinol (THC) in the United States. This legislative shift catalyzed both public and scientific interest in CBD’s potential health benefits. However, the rapid expansion of the CBD market has considerably outpaced rigorous scientific research, leaving many health claims largely unsubstantiated.

While preclinical studies suggest that CBD may exert antitumorigenic effects in colorectal cancer (CRC) by modulating cell proliferation, apoptosis, and inflammation, clinical evidence supporting these effects remains limited.

This review critically examines the current evidence on the role of CBD in colorectal tumorigenesis, with particular attention to its molecular mechanisms and interactions with the serotonergic system-a signaling pathway implicated in the development of CRC and possessing potential dual anti- and pro-tumorigenic properties. By influencing the serotonergic system, CBD may confer both protective and potentially deleterious effects during CRC development.

This review underscores the need for further research to elucidate the complex mechanisms of CBD in colorectal tumorigenesis and to evaluate its therapeutic potential in clinical settings. Understanding these interactions could pave the way for novel prevention and treatment strategies, optimizing the anticancer efficacy of CBD while mitigating unintended risks.”

https://pubmed.ncbi.nlm.nih.gov/40710186/

“Since hemp-derived cannabidiol products with less than 0.3% tetrahydrocannabinol became legal in 2018 in the United States, public interest in their health benefits has grown rapidly. However, scientific research has not kept pace, and many of the claimed benefits remain unproven.

Early preclinical studies suggest that cannabidiol may help to combat colorectal cancer by influencing how cancer cells grow and die. One of the possible mechanisms is through its interaction with the body’s serotonergic system—a pathway that can have both helpful and harmful effects on cancer development.

This review summarizes current scientific findings and emphasizes the need for more research to determine how cannabidiol works in the body and whether it is truly safe and effective for preventing or treating colorectal cancer. It offers important insights into the potentially dual effects of cannabidiol in the development of colorectal cancer amid its rapidly expanding use in health and wellness.”

https://www.mdpi.com/1718-7729/32/7/375