{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:44:29Z","timestamp":1784130269668,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010438","name":"Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010438","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["Acta Biochim. Pol."],"abstract":"<jats:p>Glioblastoma remains one of the most aggressive and treatment-resistant malignancies. Current treatment options, such as radio- and chemotherapy, induce oxidative stress-mediated DNA damage leading to cancer cell death, but are also neurotoxic and not efficient in long term. Our study investigated the effects of cannabidiol, celecoxib and 2,5-dimethylcelecoxib, individually and in combinations, on U-138 MG glioblastoma cell survival, oxidative stress, canonical and non-canonical Nrf2 pathway activation, cell migration and apoptosis. Using the MTT and flow cytometry assay we found that the analyzed compounds and their combinations induce dose-dependent, synergistic, and oxidative stress-related cytotoxicity, with minimal impact (at the concentrations exhibiting anti-cancer effects) on non-cancerous human astrocyte (HA) cell line. The Nrf2 ELISA assay was used for the analysis of the nuclear binding of the nuclear factor-2 erythroid related factor-2 (Nrf2), which followed by the RT-qPCR and Western blot analysis, confirmed the antioxidant response of cells to the applied treatments. Diminished migratory potential, and increase of the autophagy-related p62, LC3 and apoptosis-related caspase-3 protein levels were also observed in response to the treatment with the analyzed compounds. Overall, our study provides evidence that cannabidiol combined with celecoxib or 2,5-dimethylcelecoxib may represent a promising strategy for glioblastoma treatment.<\/jats:p>","DOI":"10.3389\/abp.2025.15062","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T05:10:09Z","timestamp":1759122609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Synergistic combination of cannabidiol and celecoxib or 2,5-dimethylcelecoxib exerts oxidative stress-mediated cytotoxicity and mitigates glioblastoma invasiveness"],"prefix":"10.3389","volume":"72","author":[{"given":"Anna","family":"Rybarczyk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Majchrzak-Celi\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violetta","family":"Krajka-Ku\u017aniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6271","DOI":"10.1038\/s41598-018-24548-z","article-title":"Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling","volume":"8","author":"Al-Rashed","year":"2018","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"680021","DOI":"10.3389\/fphar.2021.680021","article-title":"Targeting neuroinflammation in brain cancer: uncovering mechanisms, pharmacological targets, and neuropharmaceutical developments","volume":"12","author":"Alghamri","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1007\/s12672-022-00556-4","article-title":"Exploring the role of Nrf2 signaling in glioblastoma multiforme","volume":"13","author":"Awuah","year":"2022","journal-title":"Discov. Oncol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3390\/pharmaceutics12030265","article-title":"Cannabinoids, blood\u2013brain barrier, and brain disposition","volume":"12","author":"Calapai","year":"2020","journal-title":"Pharmaceutics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"7525","DOI":"10.3390\/ijms25147525","article-title":"Enhancing therapeutic approaches in glioblastoma with pro-oxidant treatments and synergistic combinations: in vitro experience of doxorubicin and photodynamic therapy","volume":"25","author":"Cesca","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/s41419-022-05044-9","article-title":"High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1\/MRP1 upregulation","volume":"13","author":"de Souza","year":"2022","journal-title":"Cell Death Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1116014","DOI":"10.3389\/fonc.2022.1116014","article-title":"Pleiotropic effects of the COX-2\/PGE2 axis in the glioblastoma tumor microenvironment","volume":"12","author":"Dean","year":"2023","journal-title":"Front. Oncol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s12032-024-02386-6","article-title":"Revisiting the antioxidant-prooxidant conundrum in cancer research","volume":"41","author":"Farhan","year":"2024","journal-title":"Med. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1186\/s12967-024-05477-0","article-title":"From bench to bedside: The application of cannabidiol in glioma","volume":"22","author":"Feng","year":"2024","journal-title":"J. Transl. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1094020","DOI":"10.3389\/fphar.2023.1094020","article-title":"Cannabidiol regulates apoptosis and autophagy in inflammation and cancer: a review","volume":"14","author":"Fu","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/antiox14010018","article-title":"Exploring the therapeutic potential of cannabidiol in U87MG cells: effects on autophagy and NRF2 pathway","volume":"14","author":"Giannotti","year":"2024","journal-title":"Antioxidants"},{"key":"B12","doi-asserted-by":"publisher","first-page":"65","DOI":"10.17161\/kjm.v12i3.11795","article-title":"Glioblastoma and increased survival with longer chemotherapy duration","volume":"12","author":"Jaoude","year":"2019","journal-title":"Kans. J. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"102754","DOI":"10.1016\/j.redox.2023.102754","article-title":"Drug-induced oxidative stress in cancer treatments: angel or devil?","volume":"63","author":"Jiang","year":"2023","journal-title":"Redox Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"720","DOI":"10.3390\/toxins14100720","article-title":"Cytotoxic effects of cannabidiol on neonatal rat cortical neurons and astrocytes: potential danger to brain development","volume":"14","author":"Juri\u010d","year":"2022","journal-title":"Toxins (Basel)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.3390\/ijms22031318","article-title":"Deciphering the role of autophagy in treatment of resistance mechanisms in glioblastoma","volume":"22","author":"Khan","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2846","DOI":"10.3390\/ijms23052846","article-title":"Recent advances in understanding Nrf2 agonism and its potential clinical application to metabolic and inflammatory diseases","volume":"23","author":"Kim","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e2300090","DOI":"10.1002\/adbi.202300090","article-title":"Neutralization of cannabidiol neurotoxicity in neuron-astrocyte sandwich coculture","volume":"7","author":"Kim","year":"2023","journal-title":"Adv. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"8779","DOI":"10.3390\/molecules27248779","article-title":"Cannabidiol and its combinations with nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit activation of NF-\u03baB signaling in vulvar squamous cell carcinoma","volume":"27","author":"Krajka-Ku\u017aniak","year":"2022","journal-title":"Molecules"},{"key":"B19","doi-asserted-by":"publisher","first-page":"747","DOI":"10.3390\/antiox9080747","article-title":"Oxidative stress-part of the solution or part of the problem in the hypoxic environment of a brain tumor","volume":"9","author":"Krawczynski","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"793328","DOI":"10.3389\/fcell.2022.793328","article-title":"Selective autophagy receptor p62\/SQSTM1, a pivotal player in stress and aging","volume":"10","author":"Kumar","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.3390\/pharmaceutics15082104","article-title":"Etoricoxib-cannabidiol combo: potential role in glioblastoma treatment and development of PLGA-based nanoparticles","volume":"15","author":"Ku\u017ami\u0144ska","year":"2023","journal-title":"Pharmaceutics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"CD013047","DOI":"10.1002\/14651858.CD013047.pub2","article-title":"Long\u2010term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma","volume":"8","author":"Lawrie","year":"2019","journal-title":"Cochrane database Syst. Rev."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.3390\/molecules29071682","article-title":"New avenues and major achievements in phytocompounds research for glioblastoma therapy","volume":"29","author":"Majchrzak-Celi\u0144ska","year":"2024","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1186\/s12885-021-08164-1","article-title":"COXIBs and 2,5-dimethylcelecoxib counteract the hyperactivated Wnt\/\u03b2-catenin pathway and COX-2\/PGE2\/EP4 signaling in glioblastoma cells","volume":"21","author":"Majchrzak-Celi\u0144ska","year":"2021","journal-title":"BMC Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"38022","DOI":"10.18632\/oncotarget.16723","article-title":"Combination therapy in combating cancer","volume":"8","author":"Mokhtari","year":"2017","journal-title":"Oncotarget"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e86806","DOI":"10.1371\/journal.pone.0086806","article-title":"Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models","volume":"9","author":"Novakova","year":"2014","journal-title":"PLOS ONE"},{"key":"B27","doi-asserted-by":"publisher","first-page":"176","DOI":"10.14348\/molcells.2023.2191","article-title":"The multi-faceted consequences of NRF2 activation throughout carcinogenesis","volume":"46","author":"Occhiuto","year":"2023","journal-title":"Mol. Cells"},{"key":"B28","doi-asserted-by":"publisher","first-page":"620677","DOI":"10.3389\/fmolb.2020.620677","article-title":"Drug resistance in glioblastoma: the two faces of oxidative stress","volume":"7","author":"Olivier","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"105281","DOI":"10.1016\/j.neuint.2022.105281","article-title":"Harnessing oxidative stress for anti-glioma therapy","volume":"154","author":"Ostrowski","year":"2022","journal-title":"Neurochem. Int."},{"key":"B30","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.wneu.2011.06.063","article-title":"The role of Nrf2 in migration and invasion of human glioma cell U251","volume":"80","author":"Pan","year":"2013","journal-title":"World Neurosurg."},{"key":"B31","doi-asserted-by":"publisher","first-page":"661","DOI":"10.3390\/ijms26020661","article-title":"Tinostamustine (EDO-S101) and its combination with celecoxib or temozolomide as a therapeutic option for adult-type diffuse gliomas","volume":"26","author":"Pawlak","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B32","first-page":"397","article-title":"When autophagy meets cancer through p62\/SQSTM1","volume":"2","author":"Puissant","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.drudis.2016.09.017","article-title":"Cyclooxygenase-2 in glioblastoma multiforme","volume":"22","author":"Qiu","year":"2017","journal-title":"Drug Discov. Today"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e0308233","DOI":"10.1371\/journal.pone.0308233","article-title":"Synergistic celecoxib and dimethyl-celecoxib combinations block cervix cancer growth through multiple mechanisms","volume":"19","author":"Robledo-Cadena","year":"2024","journal-title":"PLOS ONE"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2573","DOI":"10.3390\/cells9122573","article-title":"Revealing temozolomide resistance mechanisms via genome-wide CRISPR libraries","volume":"9","author":"Rocha","year":"2020","journal-title":"Cells"},{"key":"B36","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1111\/cei.13668","article-title":"Neuroinflammation and immunoregulation in glioblastoma and brain metastases: recent developments in imaging approaches","volume":"206","author":"Roesler","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.3390\/antiox12122052","article-title":"Targeting Nrf2 signaling pathway in cancer prevention and treatment: the role of cannabis compounds","volume":"12","author":"Rybarczyk","year":"","journal-title":"Antioxidants (Basel)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"207","DOI":"10.32383\/appdr\/163414","article-title":"The application of cannabidiol in the treatment of glioblastoma","volume":"80","author":"Rybarczyk","year":"","journal-title":"Acta Poloniae Pharm. - Drug Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1117\/1.JBO.25.3.036502","article-title":"Metabolic mapping of glioblastoma stem cells reveals NADH fluxes associated with glioblastoma phenotype and survival","volume":"25","author":"Schroeder","year":"2020","journal-title":"J. Biomed. Opt."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e1601","DOI":"10.1038\/cddis.2014.566","article-title":"Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma","volume":"6","author":"Singer","year":"2015","journal-title":"Cell Death Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.3389\/fphar.2018.01536","article-title":"Contribution of Nrf2 modulation to the mechanism of action of analgesic and anti-inflammatory drugs in pre-clinical and clinical stages","volume":"9","author":"Staurengo-Ferrari","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"115805","DOI":"10.1016\/j.biopha.2023.115805","article-title":"Therapeutic potentials of cannabidiol: focus on the Nrf2 signaling pathway","volume":"168","author":"Talebi","year":"2023","journal-title":"Biomed. and Pharmacother."},{"key":"B43","doi-asserted-by":"publisher","first-page":"5552226","DOI":"10.1155\/2021\/5552226","article-title":"Therapeutic potential of RTA 404 in human brain malignant glioma cell lines via cell cycle arrest via p21\/AKT signaling","volume":"2021","author":"Tsai","year":"2021","journal-title":"BioMed Res. Int."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1083\/jcb.201708007","article-title":"Superoxide dismutases: dual roles in controlling ROS damage and regulating ROS signaling","volume":"217","author":"Wang","year":"2018","journal-title":"J. Cell Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.gpb.2022.01.004","article-title":"SynergyFinder plus: toward better interpretation and annotation of drug combination screening datasets","volume":"20","author":"Zheng","year":"2022","journal-title":"Genomics, Proteomics and Bioinforma."},{"key":"B46","doi-asserted-by":"publisher","first-page":"633","DOI":"10.3389\/fneur.2018.00633","article-title":"Protective effect of celecoxib on early postoperative cognitive dysfunction in geriatric patients","volume":"9","author":"Zhu","year":"2018","journal-title":"Front. Neurol."}],"container-title":["Acta Biochimica Polonica"],"original-title":[],"link":[{"URL":"https:\/\/www.frontierspartnerships.org\/articles\/10.3389\/abp.2025.15062\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T05:10:10Z","timestamp":1759122610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontierspartnerships.org\/articles\/10.3389\/abp.2025.15062\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":46,"alternative-id":["10.3389\/abp.2025.15062"],"URL":"https:\/\/doi.org\/10.3389\/abp.2025.15062","relation":{},"ISSN":["1734-154X"],"issn-type":[{"value":"1734-154X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]},"article-number":"15062"}}