“Cancer remains a major global health challenge, necessitating new, effective therapies. Phytocannabinoids from Cannabis sativa L. show significant anticancer potential, yet their natural scarcity limits research and development.
This study presents an innovative extract engineering approach to generate rare varin-type cannabinoids from abundant precursors. Through this strategy, nine cannabinoid analogues were synthesised, including four rare varin-type compounds, and screened against five human cancer cell lines.
Among them, cannabinovarin (CBNV) and Δ6a,10a-THCV exhibited potent cytotoxicity against breast (MCF-7) and colon (HCT-116) cancer cells, with IC50 values of 15-30 µM. Mechanistic investigations revealed apoptosis induction via mitochondrial membrane disruption and reactive oxygen species generation.
These findings establish extract engineering as a rapid and efficient route to access rare cannabinoids, highlighting CBNV and Δ6a,10a-THCV as promising anticancer leads for further mechanistic and in vivo evaluation.”
“Redox homeostasis is crucial for cancer cell survival and resistance to therapy.
The transcription factor NRF2, a master regulator of antioxidant and metabolic genes, is often upregulated in tumors to mitigate oxidative stress. Although NRF2 stability is canonically governed by KEAP1-CUL3-proteasome degradation, emerging evidence implicates lysosomal and autophagic pathways in non-canonical NRF2 turnover. The mechanisms by which these alternative pathways are engaged during chronic oxidative signaling remain unclear.
We investigated whether sustained activation of the redox-sensitive ion channel TRPA1 by cannabidiol (CBD) disrupts redox homeostasis and promotes NRF2 degradation in colorectal cancer models.
Using five independent CRC cell lines (RKO, HCT116, HT29, SW480, and MC38), we assessed reactive oxygen species (ROS), mitochondrial function, autophagy, and NRF2 protein dynamics through biochemical assays, lysosomal fractionation, and imaging. Xenograft models were used for in vivo validation.
Chronic TRPA1 activation induced a biphasic ROS response, characterized by an early increase linked to mitochondrial Ca2+ influx and a delayed ROS surge associated with mitochondrial dysfunction. This oxidative trajectory initially stabilized but subsequently led to its degradation after 24 h via a KEAP1-independent, autophagy-lysosome pathway. Proteasome inhibition failed to rescue NRF2, whereas bafilomycin A1 restored its levels and blocked co-localization with lysosomal markers (e.g., LAMP2A).
Importantly, CBD-induced TRPA1 activation sensitized CRC cells to oxaliplatin, triggering apoptotic-not senescent-cell death. These effects were dose-dependent and consistent across all tested cell lines.
Our findings reveal a non-canonical bioelectric-lysosomal axis that links TRPA1 activity to NRF2 destabilization in colorectal cancer. This work expands the understanding of NRF2 proteostasis under sustained oxidative stress and highlights TRPA1 as a tractable redox-modulating target for overcoming chemoresistance.”
“In simple terms, this mechanism describes a way to disarm the cancer cells’ defense shield (Nrf2) by using TRPA1 activation, thereby making them easier to kill, potentially in combination with standard chemotherapies like oxaliplatin.”
“Colon adenocarcinoma (COAD) is characterized by the metabolic reprogramming, such as the Warburg effect, which drives tumor progression and immunosuppression. Hypoxia-inducible factor 1 (HIF-1) and lactate dehydrogenase A (LDHA) are critical regulators of this metabolic shift, but existing therapies are insufficiently specific to it.
This study investigates the antitumor mechanisms of cannabidiol, a non-psychoactive phytocannabinoid, by using integrative multi-omics and functional validation.
Single-cell transcriptomics revealed that cannabidiol reduced tumor cell proportions and suppressed glycolytic activity in COAD.
Network pharmacology identified PTGS2 as a central target, with proteomic data confirming its overexpression in COAD tissues and association with poor prognosis. In vitro, cannabidiol inhibited COAD cell proliferation, migration, and colony formation while downregulating HIF-1[Formula: see text], LDHA, and GLUT1 expression.
Metabolic assays demonstrated associated dose-dependent reductions in ATP production, glucose uptake, and lactate levels. Rescue experiments using the HIF-1agonist DMOG partially reversed cannabidiol’s antiglycolytic and antitumor effects, and thus confirmed pathway dependency. Synergy with the glycolysis inhibitor 2-DG enhanced therapeutic efficacy, which highlighted cannabidiol’s potential to overcome metabolic resistance.
These findings establish cannabidiol as a novel inhibitor of HIF-1/LDHA-driven glycolysis, and thus provide a translational strategy for metabolic vulnerability in COAD.”
“The phrase “Cannabidiol Reprograms Glucose Metabolism in Colorectal Adenocarcinoma by Targeting HIF-1α/LDHA Pathway” means that cannabidiol (CBD) helps fight colon cancer cells by altering how they use glucose (sugar) for energy, specifically by interfering with a key biological pathway involving the proteins HIF-1α and LDHA.”
“In summary, the study found that CBD acts as a novel inhibitor of the HIF-1α/LDHA pathway, suppressing the abnormal glucose metabolism essential for colorectal cancer growth and providing a potential therapeutic strategy for treatment.”
“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.”
“Background/objectives: Colorectal cancer (CRC) remains a significant global health concern, with limited treatment options for metastatic stage 4 CRC. Fibroblast Growth Factor Receptor (FGFR) is a promising therapeutic target in CRC, while cannabidiol (CBD) has shown potential for inducing cell death and overcoming drug resistance. This study evaluates the efficacy of FGFR inhibitors and explores the synergistic effects of combining FGFR inhibitors with CBD in inducing apoptosis in CRC cells.
Methods: Cannabidiol and FGFR inhibitors were applied, and protein expression was analyzed via Western blot. Cell viability was assessed using the WST-1 assay, while apoptosis was measured through flow cytometry using Annexin V-FITC/PI staining. CHOP-specific siRNA transfection was performed to study gene silencing effects, followed by RNA sequencing for differential expression and pathway analysis. Statistical significance was determined using ANOVA and t-tests, with p < 0.05.
Results: FGFR expression patterns were confirmed in various cancer cell lines, with NCI-H716 showing high FGFR2 expression. Treatment with CBD (4 µM) and AZD4547 (10 nM) resulted in significant cell death, especially when used in combination, indicating the effectiveness of this combined therapy. Increased apoptosis in NCI-H716 cells was confirmed with the combined treatment. RNA sequencing and heatmap analysis suggested that ER stress might be related to the observed synergistic effect. The role of ER stress in the combination-induced apoptosis of NCI-H716 cells was further validated.
Conclusions: The combination of FGFR inhibitors and cannabidiol exhibited a synergistic effect in inducing cell death in colorectal cancer cells, likely through the ER stress pathway. This study supports the potential of combined FGFR inhibitor and CBD therapy as a promising strategy for enhancing anticancer effects in CRC.”
“In conclusion, the data from this preclinical study indicate that the combination of cannabidiol (CBD) and FGFR inhibitors such as AZD4547 represents a potential therapeutic approach for metastatic colorectal cancer (CRC). This synergistic effect could help address resistance mechanisms that currently limit the efficacy of anticancer drugs. Our findings also suggest that ER stress-mediated apoptosis may be an important mechanism underlying this synergy. While these results are encouraging, further validation in appropriate preclinical animal models and, ultimately, clinical studies will be essential to confirm efficacy, assess safety, and determine the translational applicability of this combination strategy.”
“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.”
“Cannabidiol (CBD) is a non-neurotoxic, phytocannabinoid from cannabis with reported medicinal properties, including antiepileptic and anti-inflammatory activity.
Several in vitro and in vivo studies have shown that CBD has antitumor potential against colorectal cancer (CRC), the third deadliest cancer in the world. However, as different mutations influence the antitumor effects and CBD can bind a variety of receptors, it is yet to be determined whether specific CRC mutations affect CBD’s efficacy in treatment of CRC.
To investigate this, we selected four CRC cell lines, including HCT116, HT-29, LS174T, and LS153, which harbor distinct mutations. Cells were treated with a range of concentrations of CBD to evaluate its cytotoxic effects and impact on cell proliferation, migration, and invasion by using a live-cell imaging system. IC50 values were then calculated for each parameter. The level of endoplasmic reticulum (ER) stress pathway markers was also measured using qRTPCR. The requirements for CB1 or CB2 receptor-medicated signaling were investigated using the selective inhibitors AM251 and SR144528, respectively.
Our results demonstrate that CBD induces apoptosis and halts proliferation, migration, and invasion of CRC cell lines in a concentration-dependent manner.
CBD showed potent antitumor effects in the tested cell lines with no obvious effect from different mutations such as KRAS, BRAF, APC, PTEN, etc. CBD also induced ER stress in CRC cells but not in healthy intestinal organoids. Cotreatment with SR144528 inhibited the effects of indicating involvement of CB2 receptor activation in the anticancer effects of CBD.
Together, these results demonstrated that CBD could be effective for CRC regardless of the underlying mutation through CB2 receptor activation.”
“The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver.
Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively.
The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).
Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis.
This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.”
“In conclusion, these findings suggest that the ECS offers a versatile approach for modulating gastrointestinal physiological aspects and treating conditions such as obesity and its complications, IBS, and CRC. Future research should refine ECS-targeted therapies to maximize their efficacy and minimize adverse effects, unlocking new opportunities for innovative treatments of disordered metabolism, inflammation, and cancer.
Clinical studies show that medical cannabis could be a valuable adjunct to cancer and treatments for inflammation, providing symptom relief and improving patients’ overall quality of life. However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”
“Background: Our recent studies have identified a link between sphingolipid metabolites and the induction of a specialized form of regulated cell death termed immunogenic cell death (ICD). We have recently demonstrated that the synthetic cannabinoid (±) 5-epi CP 55,940 (5-epi) stimulates the accumulation of ceramide (Cer), and that inhibition of sphingosine kinase 1 (SphK1) enhances Cer accumulation and ICD-induction in human colorectal cancer (CRC) cell lines.
Methods: We employed flow-cytometric, western blot analyses, pharmacological inhibitors of the sphingolipid metabolic pathway and small molecule agonists and antagonists of the CB receptors to further analyze the mechanism by which 5-epi induces Cer accumulation.
Results: Herein, and report that 5-epi induces de novo synthesis of Cer primarily through engagement of the cannabinoid receptor 2 (CB2) and depletion of intracellular calcium levels. Moreover, we report that 5-epi stimulates Cer synthesis through dysregulation of the endogenous inhibitor of the de novo Cer pathway, ORMDL3. We also observed a remarkable and specific accumulation of one Cer species, C20:4 Cer, generated predominantly by ceramide synthase 4, as a key factor required for 5-epi-induced ICD.
Conclusions: Together, these data indicate that engagement of CB2, by 5-epi, alters regulation of the de novo ceramide synthesis pathway to generate Cer species that mediate ICD.”
“Mounting evidence demonstrates that cannabinoids have anti-cancer properties.
The mechanism by which the cannabinoids induce cell death is still unclear. However, increased intracellular production of the sphingolipid, ceramide, seems to be a commonality. We recently demonstrated that a synthetic cannabinoid induced a specialized form of cell death that is known to activate the patient’s immune system, termed immunogenic cell death (ICD). Herein, we provide evidence of the mechanism by which synthetic cannabinoids increase ceramide production and demonstrate that ceramide is required for ICD.
These findings strengthen the evidence that cannabinoids are effective anti-cancer agents and, importantly, suggest that they may help to recruit the immune system to fight the patient’s tumor.”
“Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and its potential therapeutic effects extend beyond its well-known antiepileptic properties. Exploring CBD and its analogues as anticancer agents has gained significant attention in recent years.
In this study, a series of novel ring-annulated analogues of CBD with oxazinyl moiety were synthesized and evaluated for their antiproliferative effect.
The analogues 4d and 4h demonstrate promising activity against breast and colorectal cancer. Furthermore, mechanistic insights revealed that the identified candidates arrest the G1 phase of the cell cycle and induce apoptosis via the mitochondrial pathway in breast cancer cell lines.
Notably, CBD ring-annulated analogues 4d or 4h exhibit enhanced solubility, better metabolic stability, and lowered cytochrome P450 (CYP) inhibition liability compared to CBD.
These multifaceted attributes highlight the potential of cannabinoid-based candidates for further preclinical development.”
