“Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, has gained significant attention for its potential therapeutic effects across various types of cancer.
This manuscript presents a systematic review of the current evidence on the application of CBD in gastrointestinal (GI) malignancies, with a focus on gastric and colorectal cancers.
The review aims to explore CBD’s mechanisms of action, including its effects on apoptosis, cell cycle regulation, angiogenesis, inflammation, and its potential to enhance the efficacy of conventional therapies. Furthermore, it examines the challenges involved in translating preclinical findings into clinical settings, such as issues related to bioavailability and regulatory hurdles.
The review also addresses future directions for the use of CBD in combination therapies and its potential to overcome resistance mechanisms in GI cancers. By analyzing the molecular pathways modulated by CBD, this manuscript seeks to offer a comprehensive understanding of its therapeutic potential, contributing to the future of GI cancer treatment.”
“The main objective of the present study was to determine the protolytic and coordination properties of two bioactive cannabinoid acids (cannabidiolic acid and cannabigerolic acid) in ethyl alcohol-water mixture (50/50, v/v).
The complexation properties of these acids with copper(II) and zinc(II) ions were determined by potentiometric and ESI-MS methods. UV-Vis absorption spectra for the copper(II) systems confirmed the speciation models with one type of complex indicating coordination with completely deprotonated dinegative ligand molecule. The occurrence of precipitation at lower pH values limited the ability to determine complexes under these conditions.
The research also aimed to identify potential biological and medicinal applications of cannabinoid acids and their complexes with zinc(II). The ability of these compounds to influence the growth of human Hs68 skin fibroblasts and AGS gastric adenocarcinoma cells was investigated. Furthermore, these structures were tested against Helicobacter pylori strains, one of the factors promoting gastric cancer development.
At concentrations that were not-toxic to healthy cells (after dilution of the solutions, the composition of the ethanol/water mixture was approximately 1/99, v/v), the ligands exhibited bacterial inhibitory activity and cytotoxic properties against AGS cancer cells. Zinc(II) complexes, on the other hand, being biologically safe for all cells, had strong antibacterial properties, both inhibitory and bactericidal.”
“Naturally occurring compounds known as plant cannabinoids or phytocannabinoids, responsible for the physiological effects of cannabis, have been used medicinally for thousands of years.”
“Cannabidiol (CBD) has shown promise in treating cancers with an inflammatory microenvironment.
Although it has been demonstrated that IL-1β induces epithelial-mesenchymal transition (EMT) of MCF-7 cells and CBD reverts this process, in restoring the epithelial non-invasive phenotype, there is limited understanding of how this cannabinoid regulates these processes.
In this work, MCF-7 cells were induced to adopt an aggressive phenotype (6D cells), which was reversed by CBD.
Then, protein expression was analyzed by mass spectrometry to compare 6D vs. MCF-7 cells and 6D+CBD vs. 6D cells proteomes. Novel proteins associated with EMT and CBD signaling were identified. Twenty-four of them were oppositely regulated by IL-1β and CBD, suggesting new points of crosstalk between the IL-1β and CBD signaling pathways.
From the data, two protein networks were constructed: one related to EMT with 58 up-regulated proteins and another with 21 related to CBD signaling. The first one showed the proteins BRCA1, MSN, and CORO1A as the key axis that contributes to the establishment of a mesenchymal phenotype. In the CBD signaling, the key axis was formed by SUPT16H, SETD2, and H2BC12, which suggests epigenetic regulation by CBD in the restoration of an epithelial phenotype of breast cancer cells, providing new targets for anticancer therapy.”
“All these results provide new important insights that could help to understand how CBD counteracts the effects of IL-1β and the restoration of the epithelial phenotype as a possible control of cancer progression.”
“Multiple investigations have shown that the different types of cannabinoids, phytocannabinoids, synthetic cannabinoids, and endocannabinoids, possess antiproliferative and anticancer properties.
The cannabinoid type-2 receptor (CB2R) has been proposed as a central player in tumor progression and has been correlated with the aggressiveness of breast cancer. Using immunocytochemistry and confocal microscopy, in the present work, we studied the expression level and subcellular localization of CB2R in two human triple-negative breast cancer (TNBC) cell lines, corresponding to early (stage I, HCC-1395) and metastatic (MDA-MB-231) stages, and they were compared with a non-tumoral mammary epithelial cell line (MCF-10A).
We found that although CB2R was detected at the plasma membrane, it was mainly localized intracellularly, with ~40-fold higher expression in both TNBC cell lines than in MCF-10A (P < 0.0001). Notably, double staining with DAPI or with the nucleoli-specific fluorescent marker (3xnls-mTurquoise2) showed that most of the CB2R overexpressed in the nucleoli of cancer cells.
This finding is supported by the fact that CB2R expression was markedly lower in mitotic cells compared to interphase cells (P < 0.0001). Interestingly, exposure of cancer cells to the specific agonist HU-308 reversed the nucleolar sequestration of CB2R while increasing the presence of the receptor in the nucleoplasm and cytoplasm (P < 0.0001). In addition, we found that this agonist reduced both the cell migration (P < 0.05-0.0001) and proliferation (P < 0.001) of TNBC cells. It remains to determine the function and signaling ability of CB2R in the nucleolus.
Although our study only includes cell lines (tumoral and non-tumoral), we consider that this feature of nucleolar sequestration of CB2R could be a potential diagnostic marker for TNBC from the early stage.”
“Triple-negative breast cancer (TNBC) is an invasive and difficult-to-treat carcinoma that represents 15-20 % of breast malignancies and is frequently diagnosed in younger women. Chemotherapy is the mainstay treatment approach.
Cannabidiol (CBD), the main non-psychoactive cannabinoid, has shown a potential anticancer activity in TNBC, enhancing the effect of conventional antineoplastics.
This research aims to develop in situ forming implants (ISFIs) as a long-acting depot formulation of CBD with potential application in TNBC. This formulation is intended to be administered in the tumor site during neoadjuvant chemotherapeutic regimens, allowing a controlled CBD release. ISFIs were elaborated with 100 mg of polycaprolactone (PCL) and 2.5 mg (2.5-CB-ISFI), 5 mg (5-CB-ISFI) or 10 mg (10-CB-ISFI) of CBD dissolved in 400 µL of NMP. All the formulations exhibited a controlled drug release for around two months. 10-CB-ISFI formulation with the highest CBD content and the most suitable CBD release profile was selected for biological studies.
This formulation inhibited the proliferation and migration of MDA-MB-231 and 4T1 cells and exerted an antiangiogenic effect in ovo. Interestingly, the antiangiogenic activity of 10-CB-ISFI was higher compared with CBD in solution administered at the same concentration, showing vascular inhibition percentages of around 80 % and 60 %, respectively.
Finally, this formulation reduced the growth of MDA-MB-231-derived tumors developed in the chorioallantoic membrane (CAM) model. The single administration of 10-CB-ISFI exhibited a similar antitumor efficacy to the daily administration of CBD in solution (≈60 % tumor growth inhibition).
Therefore, the injectable depot formulation of CBD developed in this work showed a promising utility in TNBC treatment.”
“Cannabinoids have been used as anti-emetic agents in cancer. However, multiple studies suggest that cannabinoids present important anti-tumor actions as well.
Estrogen receptor-positive (ER+) breast cancer is the most diagnosed breast cancer subtype, and despite the success of endocrine therapy, endocrine resistance development is a major challenge, demanding the discovery or implementation of alternative therapeutic approaches.
In line with this, and following our previous work, the benefits of combining the aromatase inhibitors (AIs) used in the clinic, anastrozole (Ana), letrozole (Let), and exemestane (Exe), with cannabinol (CBN) were evaluated. Experiments were performed in MCF-7aro cells and spheroids to assess activity against specific molecular targets and underlying mechanisms of action.
Among the three AIs studied, only the combination of CBN with Exe induced a significant beneficial impact on viability and growth of ER+ breast cancer cells and spheroids.
Our results demonstrated that this combination was more effective than Exe in preventing the expression of aromatase and in modulating ERα and androgen receptor (AR) activity.
In fact, the results revealed that CBN can prevent de novo synthesis of aromatase, surpass Exe’s weak estrogen-like effect, and avoid the unfavorable overexpression of AR. By comparing these two therapeutic strategies, as well as the previously studied combination of Exe plus cannabidiol (CBD), differential transcriptome profiles were detected, which may help to better understand the mechanism of action of cannabinoids and disclose their full potential in breast cancer treatment.
In conclusion, this study strengthens the hypothesis that cannabinoids are important anti-cancer agents with attractive co-adjuvant properties.”
“Background: Combined radiation and wound skin injury (RW) are frequently observed in patients undergoing tumor surgery plus radiotherapy, and but specific treatment is lacking. Chitosan (CS) and carboxymethyl cellulose (CMC) are commonly used to prepare hydrogel with good biocompatibility and low toxicity.
Cannabidiol (CBD) has presented anti-inflammatory, antioxidant, and neuroprotective properties.
Methods: CMC, CS, and CBD were used and designed for three types of hydrogels (CMC/CS2/CBD, CMC/CS3/CBD, CMC/CS4/CBD) with different ratios of CMC and CS based on previous report and our preliminary experiments. The CMC/CS/CBD hydrogel was synthesized using electrostatic interaction without chemical crosslinking, characterized via fourier transform infrared (FT-IR), and tested for mechanical properties, swelling behavior, biocompatibility, antioxidant activity, cytotoxicity, and hemocompatibility. 60Co γ irradiation (5 Gy, 0.62 Gy/min) combined with 1 cm circular trauma was applied to establish RW mice model. Topical applications of CMC/CS3, CMC/CS2/CBD, CMC/CS3/CBD were used to treat RW injury once a day for 10 consecutive days. The mice were euthanized 7, 14, 21 days after radiation, and samples were collected.
Results: FT-IR confirmed the successful formation of a polyelectrolyte network. The CMC/CS3/CBD hydrogel exhibited optimal mechanical strength, rapid gelation, high swelling capacity, and excellent biocompatibility. Both CMC/CS2/CBD and CMC/CS3/CBD hydrogels effectively improved RW injury 7, 14, 21 days after radiation. Reduced inflammation and increased collagen production were observed the two groups. The significant increased expression of interleukin (IL)-1β, IL-22, IL-17A, IL-6, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, CC motif chemokine ligand (CCL)2, CCL3, CCL4, CCL5, CCL11 in the RW group was greatly inhibited after treatment with CMC/CS3/CBD hydrogel. Transcriptome analysis revealed the hydrogel’s impact on lipid metabolism and epithelial differentiation pathways.
Conclusions: By integrating CBD into a CMC/CS-based hydrogel without using toxic crosslinkers, this study provides a novel, biomaterial-based, biocompatible approach for RW injury. These findings pave the way for future clinical application of CMC/CS3/CBD hydrogel in RW injury.”
“We developed an injectable CMC/CS/CBD hydrogel for the treatment of RW injuries. The hydrogel was fabricated via electrostatic self-assembly, eliminating the need for toxic chemical crosslinkers, exhibiting excellent biocompatibility and low cytotoxicity. Our work firstly integrated CBD into a hydrogel matrix specifically for RW treatment, and confirmed its ability to suppress inflammation and regulate macrophage polarization.”
“Purpose: Recent advancements in psycho-neuro-endocrine-immunology indicate that numerous noncommunicable diseases (NCDs) originate from disruptions in the cytokine immune network, resulting in chronic inflammatory responses. This persistent low-degree inflammation is attributed to deficiencies in crucial endogenous anti-inflammatory neuroendocrine systems, including the pineal gland, the endocannabinoid system, and the angiotensin-converting enzyme 2 / angiotensin 1-7 axis.
The administration of pineal methoxyindoles (melatonin, 5-methoxytryptamine), cannabinoids, and angiotensin 1-7 may entail potential therapeutic benefits for NCDs, particularly for patients who do not respond to conventional treatments.
Patients and methods: This study evaluates the safety and efficacy of a neuroimmune regimen comprising melatonin (100 mg/day at night), 5-methoxytryptamine (30 mg in the early afternoon), angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily) in 306 patients with NCDs, including advanced cancer, autoimmune diseases, neurodegenerative disorders, depression, and cardiovascular disease.
Results: The neuroimmune regimen successfully halted cancer progression in 68% of cancer patients, who also reported improvements in mood, sleep, and relief from anxiety, pain, and fatigue. In patients with autoimmune diseases, the treatment effectively controlled the disease process, remarkable in cases of multiple sclerosis. Additionally, positive outcomes were observed in patients with Parkinson’s disease, Alzheimer’s disease, and depression.
Conclusion: Randomized controlled trials are required to assess this therapeutic approach for NCDs that includes endogenous neuroendocrine molecules regulating immune responses in an anti-inflammatory manner.”
“This study highlights the potential of leveraging endogenous molecules to treat NCDs by modulating cell proliferation, inflammation, immune responses, metabolism, and neurological functions. The findings suggest that a neuroimmune regimen incorporating melatonin, angiotensin 1–7, and other bioactive compounds could offer a low-cost, minimally toxic therapeutic approach.”
“The search for more effective and safer cancer therapies has led to an increasing interest in combination treatments that use well-established agents.
Here we explore the potential of cannabidiol (CBD), a compound derived from cannabis, to enhance the anticancer effects of etoposide in non-small cell lung cancer (NSCLC). Although CBD is primarily used to manage childhood epilepsy, its broader therapeutic applications are being actively investigated, particularly in oncology.
Our results revealed that, among various tested chemotherapeutic drugs, etoposide showed the most significant reduction in NSCLC cell viability when combined with CBD.
To understand this synergistic effect, we conducted extensive transcriptomic and proteomic profiling, which showed that the combination of CBD and etoposide upregulated genes associated with autophagic cell death while downregulating key oncogenes known to drive tumor progression. This dual effect on cell death and oncogene suppression was mediated by inactivation of the PI3K-AKT-mTOR signaling pathway, a crucial regulator of cell growth and survival, and was found to be dependent on the p53 status.
Interestingly, our analysis revealed that this combination therapy did not rely on traditional cannabinoid receptors or transient receptor potential cation channels, indicating that CBD exerts its anticancer effects through novel, noncanonical mechanisms.
The findings suggest that the combination of CBD with etoposide could represent a groundbreaking approach to NSCLC treatment, particularly in cases where conventional therapies fail. By inducing autophagic cell death and inhibiting oncogenic pathways, this therapeutic strategy offers a promising new avenue for enhancing treatment efficacy in NSCLC, especially in tumors with p53 function.”
“In conclusion, the combination of CBD and etoposide presents a compelling therapeutic strategy for NSCLC, leveraging mechanisms of autophagy, apoptosis and oncogene suppression. These findings not only provide a strong rationale for further exploration in preclinical and clinical settings but also suggest the potential to address key challenges in NSCLC treatment, such as drug resistance and the limitations of existing therapies. Furthermore, this combination therapy holds particular promise for patients with p53 mutations or those who have developed resistance to EGFR inhibitors (for example, osimertinib) or ALK-targeted drugs (for example, alectinib), providing a promising alternative approach for improving the outcomes of patients with NSCLC.”
“The Endocannabinoid System (ECS) plays a critical role in maintaining physiological homeostasis, influencing a range of processes such as neuroprotection, inflammation, energy metabolism, and immune responses.
Comprising cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation, the ECS has attracted increasing attention in cancer research. Cannabinoid receptor activation has been associated with the regulation of cancer-related processes, including cell proliferation, apoptosis, and angiogenesis, suggesting that the ECS may have a role in tumor progression and cancer treatment.
Preclinical studies have shown that cannabinoids, through their interaction with CB1 and CB2 receptors, can inhibit tumor cell growth, induce programmed cell death, and suppress the formation of new blood vessels in various cancer models.
Despite these encouraging findings, the clinical translation of ECS-targeted therapies remains in its early stages. The complexity of tumor heterogeneity, the variability in patient responses, and the challenges associated with the pharmacokinetics of cannabinoids are significant obstacles to the broader application of these findings in clinical settings.
This review provides an overview of the current understanding of the ECS’s involvement in cancer biology, focusing on key mechanisms by which it may influence carcinogenesis. Additionally, we discuss the therapeutic potential of targeting the ECS in cancer treatment, while highlighting the limitations and uncertainties that need to be addressed through ongoing research.”
