The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target. Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2. Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells—influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support. In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.

Background/Objectives: Glioblastoma multiforme (GBM) therapy efficacy remains limited due to the poor blood-brain barrier-penetrating power of drugs as well as dysregulated cellular signaling pathways of tumor cells leading to drug resistance. Novel drug delivery systems such as liposome-based nanoformulations improve the bioavailability and stability of water-insoluble drugs, while co-delivery of two anti-cancer compounds can further increase their anti-tumor effectiveness due to synergistic effects. Thus, the aim of this study was to obtain liposomal nanoformulations encapsulating cannabidiol (CBD), celecoxib (CELE), and 2,5-dimethylcelecoxib (DMC) and their combinations and to verify their anti-GBM properties. Methods: Five liposomal nanoformulations were obtained using a modified thin-film hydration technique. Two GBM cell lines and non-cancerous astrocytes were used for the biological evaluation of the tested nanoformulations. The cytotoxicity experiments were performed using the MTT assay, whereas flow cytometry-based analysis assessed the effect of the liposomes on apoptosis, cell cycle distribution, and oxidative stress. To determine the impact of the tested nanoformulations on Nrf2, Wnt/β-catenin, and NF-κB signaling pathways, qPCR, Western blot and ELISA techniques were used. Results: The findings of this study demonstrate that liposomal nanoformulations containing CBD, CELE, and DMC exhibit significant anti-GBM activity, particularly through the induction of apoptosis and oxidative stress and modulation of the key signaling pathways. Although no clear synergistic/additive effects were observed between CBD and CELE or DMC when co-loaded in nanoformulations, the combination of CBD and CELE effectively suppressed Wnt/β-catenin and NF-κB signaling and activated the Nrf2 pathway. These results support the therapeutic potential of liposome-based co-delivery of CBD and CELE in GBM therapy. However, further in vivo studies are warranted to determine these nanoformulations’ translational relevance and clinical applicability.

Malignant gliomas, including glioblastoma multiforme (GBM) and grade 4 astrocytoma, are the most common types of brain tumors in adults. Standard treatment for gliomas includes adjuvant chemotherapy, typically based on temozolomide, combined with radiotherapy. However, its effectiveness is severely hindered by the limited ability of drugs to cross the blood–brain barrier and by the hyperactivation of the canonical Wnt signaling pathway, which drives tumor cell survival. Therefore, innovative drug combinations and novel delivery strategies are crucial for overcoming these barriers. Polymeric micelles represent a promising approach for enhancing drug delivery to brain tumors. This study aimed to obtain micelles containing cannabidiol (CBD), celecoxib (CELE), and temozolomide (TMZ), as well as their combinations, and to verify their anti-glioma properties. The study involved optimizing the micelle composition, incorporating active ingredients, and assessing the temporal stability of the resulting nanocarriers under varying temperature conditions. The GBM cell line U-138 MG and astrocytoma cell line U-87 MG were used to evaluate the biologic effects of the tested micelles. Cytotoxicity was assessed using the MTT assay, and flow cytometry was used to analyze the effect of the micelles on apoptosis. Western blot analysis was employed to assess the impact of the tested nanoformulations on the Wnt/β-catenin signaling pathway. The optimized micelles demonstrated strong cytotoxic and proapoptotic effects, accompanied by attenuation of the Wnt/β-catenin pathway. These preliminary findings support the therapeutic potential of polymeric micelles for treating malignant gliomas; however, further in vitro and in vivo studies are required to confirm their clinical applicability.

Inflammation contributes to the rapid progression of high-grade gliomas, indicating that anti-inflammatory strategies targeting NF-κB signaling may offer therapeutic benefit. Cannabidiol (CBD) and celecoxib (CELE) are hydrophobic pharmacological agents whose formulation in lipid carriers may support their combined biological evaluation. In this proof-of-concept study, we investigated liposomal formulations containing CBD, CELE, or both compounds in U-87 MG high-grade glioma cells and in a subcutaneous xenograft model. We assessed cytotoxicity, apoptosis, oxidative stress, Nrf2-dependent responses, NF-κB-centered inflammatory networks, tumor cell invasive properties, and Wnt/β-catenin pathway activity. The nanoformulations induced reactive oxygen species generation by 1.8-fold, which was accompanied by Nrf2 activation. Cationic formulations loaded with the compounds produced more pronounced pro-apoptotic effects (up to 39%) than POPC liposomes, although both types reduced the nuclear translocation of the NF-κB p65 subunit. The CBD + CELE-containing formulation showed a trend toward reduced tumor progression in mice. It is important to note that the in vitro and in vivo nanoformulations were physicochemically related, but not identical, and the in vivo experiment should be interpreted as a preliminary assessment after intratumoral administration. Overall, cationic liposomes co-loaded with CBD + CELE represent a promising platform for further optimization aimed at coordinated modulation of inflammatory, oxidative, and proliferative pathways in glioma. However, additional studies, including tissue distribution, release kinetics, and efficacy in orthotopic glioma models, are needed to fully verify their translational potential.

Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. Among novel therapeutic strategies, the development of two‑drug hybrid molecules -single entities composed of two pharmacophores - has emerged as a promising approach. Principal component analysis of structural and physicochemical descriptors of cannabinoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and CBD–NSAID hybrids revealed distinct physicochemical profiles for each group, suggesting that the hybrids may possess new and potentially advantageous functionalities. Thus, this study aimed to synthesize and biologically characterize five novel hybrid molecules composed of cannabidiol (CBD) and selected NSAIDs: ibuprofen (IBU), ketoprofen (KET), naproxen (NAP), indomethacin (INDO), and sulindac (SUL). Cytotoxicity analyses (MTT assay) in GBM T98G and U-138 MG cells, as well as non‑cancerous MRC‑5 cells, demonstrated potent anti‑GBM activity of the hybrids - particularly CBD–IBU - together with a more favorable toxicity profile toward normal cells. Using the Luminex MAGPIX® multiplex immunoassay system, we observed that the hybrids modulate key GBM‑related signaling molecules, including NF‑κB, STAT3, STAT5, AKT, p70, p70S6K, JNK, ERK1/2, p38, and CREB. Additionally, in silico docking studies revealed strong predicted binding of the hybrids - especially CBD–SUL - to the Keap1 Kelch domain. In conclusion, our study provides preliminary evidence supporting the anti‑GBM potential of these novel CBD–NSAID hybrid molecules. However, further mechanistic studies and in‑depth in vivo evaluation are needed to fully validate their therapeutic applicability.