“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“Rationale: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer that typically affects women ages 20 to 50, presenting as an asymptomatic neck mass. Treatment with total or partial thyroidectomy shows an excellent prognosis. However, investigation of non-invasive therapeutic options with minimal adverse effects is ongoing. This study seeks to investigate the K1 cell line, which consists of PTC cells obtained from metastatic tumors of well-differentiated PTC.
Objective: Our investigation focuses on a cannabinoid-based product (named BRF1-A) and its potential anti-cancer effects through modulation of gene expression. We investigated its effects on gene expression of p53, c-Myc, and BCL-2 in K1 papillary thyroid cancer cells.
Methods: BRF1A was co-cultured with K1 cell line (1 × 106 cells/ml) and incubated at 37°C under 5% CO2 for 24 and 48 hours. After the culture time points, the cells were harvested, and cell viability was determined via trypan blue exclusion assay. Using qRT-PCR, we determined the effect on the gene expression of TP53, c-Myc, and BCL-2.
Results: Results show that the BRF1A decreased the viability of K1 PTC cells in a dose and time-dependent manner. Within 24 hours, the cannabinoid- containing product increased the gene expression of TP53 and decreased the gene expression of BCL-2 and c-Myc in K1 PTC cells.
Conclusion: The results suggest that the cannabinoid-containing product BRF1A interacts as a potential regulator in well-differentiated thyroid cancer with the upregulation of p53 and downregulation of BLC-2 and c-Myc. Further in vitro and in vivo studies are needed to understand the exact mechanism and therapeutic potential of the cannabinoid-containing products in papillary thyroid cancer.”
“Our results suggest that a cannabinoid-containing product, BRF1A, functions as a potential regulator of thyroid cancer cells by upregulating tumor suppressor p53 and downregulating c-Myc and BCL-2. BRF1A may have potential therapeutic benefits in the treatment of thyroid carcinoma and warrants further investigation in vitro and in vivo of its potential mechanism.”
“Background: Osteosarcoma remains a therapeutic challenge due to its aggressive behavior and high metastatic potential, necessitating exploration of novel treatment modalities. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with emerging anticancer properties, has shown promise in preclinical cancer models. However, its mechanisms of action in osteosarcoma remain incompletely understood. This study systematically investigates the antitumor effects of CBD on osteosarcoma and elucidates its molecular targets within the TNF-α/NF-κB/CCL5 signaling axis.
Methods: The effective concentration of CBD was determined using the CCK-8 assay. Functional assays (EdU proliferation, Transwell migration/invasion, and scratch wound healing) evaluated its impact on osteosarcoma cell malignancy. A mouse xenograft model assessed in vivo efficacy. Network pharmacology and RNA-seq identified key pathways, which were validated via ELISA, qRT-PCR, and western blot. Molecular interactions were confirmed through CETSA, SPR, ITC, and molecular docking analyses targeting p65 (NF-κB subunit).
Results: CBD potently suppressed osteosarcoma cell proliferation, migration, and invasion while inhibiting xenograft tumor growth in vivo. Mechanistically, CBD disrupted the TNF-α/NF-κB/CCL5 axis by directly binding p65, thereby attenuating NF-κB-mediated transcriptional activation of CCL5. Notably, CBD abrogated a p65-CCL5 positive feedback loop that perpetuates inflammatory signaling, a novel finding linking CBD’s effects to inflammatory cascade disruption in osteosarcoma.
Conclusion: This study provides the first evidence that CBD inhibits osteosarcoma progression by targeting the TNF-α/NF-κB/CCL5 axis, disrupting a coordinated inflammatory-proliferative cascade. These findings position CBD as a promising therapeutic candidate for osteosarcoma, warranting further clinical investigation.”
“Classical cisplatin-based chemotherapeutic drugs are widely used in clinical practice. In recent years, novel platinum-based antitumor drugs have focused on replacing classical cisplatin-like Pt(II) complexes with relatively inert Pt(IV) prodrugs to overcome drug resistance and reduce toxic side effects.
Based on the excellent physiological and pharmacological activities of cannabidiol (CBD), this study designed and synthesized novel Pt(IV) prodrugs W1-W6, which are axial conjugates of cisplatin with CBD and specific active small molecules.
These prodrugs demonstrated more significant antitumor activity against tested tumor cell lines. Among them, the multifunctional Pt(IV) prodrug W5, conjugated with CBD and the PDK inhibitor DCA, exhibited excellent activity against both platinum-sensitive and cisplatin-resistant tumor strains.
The IC50 value of W5 for the A549R tumor strain was 8.53 ± 0.76 μM, significantly higher than that of the cisplatin group and 3.64 times the activity of CBD alone, demonstrating strong synergistic antitumor activity and potential to overcome cisplatin resistance. W5 is reduced by GSH in A549R cells, releasing CBD and Pt(II). Pt(II) binds to DNA, inducing damage and inhibiting repair, while CBD activates pro-apoptotic proteins, leading to mitochondrial dysfunction. Simultaneously, W5 reduces the levels of ROS scavengers, triggering endoplasmic reticulum dysfunction. These three mechanisms synergistically promote tumor cell apoptosis and overcome drug resistance.
This design integrates multiple mechanisms through axial functionalization, breaking through the limitation of traditional platinum drugs targeting DNA alone, and achieves synergistic effects by regulating metabolism and intervening in the immune microenvironment.”
“Cannabidiol (CBD) is another high-content non-psychoactive component in cannabis extracts, possessing functions such as antitumor, antiepileptic, anticonvulsant, anxiolytic, and anti-inflammatory properties [[12], [13], [14]]. Research indicates that cannabidiol, as a hydrophobic molecule, can easily cross the blood-brain barrier to reach brain tumor sites [15], enhancing interactions with the endocannabinoid system (ECS) to alleviate pain and promote immune cell regulation [16], thereby increasing the expression of complexes that help the immune system recognize cancer.”
“Background: Medical cannabis consumption is rising, but limited evidence informs the safety and efficacy of cannabis use in cancer patients. A national survey of oncology trainees found that most fellows felt insufficiently informed to make clinical recommendations about cannabis.
Aim: In this secondary analysis, we aimed to measure how frequently trainees recommend in favor of cannabis and determine factors influencing this clinical practice.
Methods: In this cross-sectional survey study for fellows enrolled in oncology training programs across the United States, an online survey assessing trainee practices regarding medical cannabis was sent to 155 oncology fellowship program directors from January – March 2021; who were asked to distribute it to their fellows. The primary outcome was the frequency with which oncology fellows recommended cannabis in the prior year.
Results: Nationally, 40 programs from 25 states participated, with 189 of 462 trainees across these programs responding (40.9% response rate). 22% (95% CI: 16.3-29.0%) of participants reported recommending medical cannabis to > 5 patients in the past year. 24% (95% CI: 18.4-30.5%) of participants had prior training in medical cannabis. Regarding participant characteristics, only prior training in medical cannabis was significantly associated with recommending cannabis to > 5 patients (RR: 2.4; 95% CI: 1.4-4.2).
Conclusions: With increasing cannabis use among patients with cancer and given that a substantial number of oncology fellows recommend its use, it is crucial that fellowship training incorporate evidence-based curricula regarding medical cannabis use to guide informed decision-making between patients and their fellow providers.”
“1 in 5 oncology fellows participating in our study recommended it to > 5 patients in the past year. Prior training in medical cannabis was the sole factor associated with higher rates of discussing and recommending its use to patients. Personalized, patient-centered care for cancer patients—and all patients—is mandatorily founded on understanding and articulating the best available evidence regarding treatment options.
Accordingly, as medical cannabis gains more widespread legal status and is increasingly considered and used by our patients, it will be of critical importance that contemporary fellowship training programs incorporate rigorous, up-to-date curricula on this subject so as to prepare their trainees to engage in well-informed discussions and shared decision-making with those for whom they care.”
“The global incidence of cancer continues to rise at an alarming rate, with annual cases projected to increase by 47% from 19.3 million in 2020 to 28.4 million by 2025.
Cannabis sativa L. was among the earliest plants investigated for potential anticancer therapies, due to its more than 100 bioactive constituents that confer notable antioxidant properties.
Hemp-derived extracts, particularly those rich in cannabidiol (CBD), exhibit notable synergistic biological effects, including the inhibition of cancer cell proliferation, angiogenesis, and metastasis, alongside the promotion of apoptosis.
These pharmacological attributes suggest that hemp oils may serve as promising alternatives or adjuncts to conventional chemotherapy, offering potential therapeutic benefits with a reduced risk of severe adverse effects.
This review discusses the current literature on hemp oils, with emphasis on their roles in cancer prevention, therapeutic efficacy, and potential toxicity in humans. Furthermore, it explores the various extraction methods employed in hemp oil production and examines their chemical compositions, offering a comprehensive understanding of the principal antioxidant constituents responsible for their bioactivity to the readers.”
“Cancer is strongly associated with oxidative stress induced by free radicals, which damage cellular components, leading to genetic mutations, the disruption of normal cellular functions, and the promotion of carcinogenesis.
Hemp oils, which are rich in natural antioxidants such as cannabinoids, flavonoids, and terpenes, have been proposed as potential mediators to lessen oxidative stress and inhibit cancer progression by neutralizing free radicals and modulating biological pathways involved in cancer development.
This review presents a comprehensive analysis of the antioxidant and anticancer properties of hemp oils, with a particular focus on their potential role in cancer prevention and treatment in humans. It also addresses extraction techniques, chemical composition, therapeutic applications, and the potential toxicological risks associated with their use.”
“Hemp oils contain a complex matrix of bioactive compounds including cannabinoids, terpenes, flavonoids, and fatty acids that act synergistically to exert antioxidant and anticancer effects. Mechanistic studies demonstrate their ability to reduce oxidative stress, induce apoptosis, inhibit angiogenesis, and target cancer stem-like cells.’
