COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress
Oxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activ...
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MDPI AG
2025-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/4/459 |
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| author | Francesca Rosaria Augello Francesca Lombardi Valeria Ciummo Alessia Ciafarone Maria Grazia Cifone Benedetta Cinque Paola Palumbo |
| author_facet | Francesca Rosaria Augello Francesca Lombardi Valeria Ciummo Alessia Ciafarone Maria Grazia Cifone Benedetta Cinque Paola Palumbo |
| author_sort | Francesca Rosaria Augello |
| collection | DOAJ |
| description | Oxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activates antioxidant defenses, protecting GBM cells from therapy-induced oxidative stress and contributing to Temozolomide (TMZ) resistance. Cyclooxygenase-2 (COX-2) plays a key role in GBM chemoresistance by modulating the tumor microenvironment and supporting a pro-survival phenotype. The impact of COX-2 inhibition by celecoxib (CXB), a selective COX-2 inhibitor, combined with TMZ on oxidative stress modulation linked to resistance was investigated in GBM primary cultures and cell lines. The drug combination CXB+TMZ was tested on TMZ-sensitive and -resistant cells, and ROS levels and Nrf2 activation were evaluated via a DCFH-DA probe and Western blotting, respectively. The oxidative stress marker malondialdehyde and antioxidant enzymes were assayed using standard methods. COX-2 inhibition combined with TMZ significantly increased ROS, while TMZ alone induced a compensatory antioxidant response, sustaining resistance. Drug combination reduced this response, restoring oxidative stress even in TMZ-resistant cells. Prostaglandin E2 reversed these effects, confirming the role of the COX-2/PGE2 axis in redox balance. Drug combination increased ROS, disrupted redox homeostasis and overcame TMZ resistance, supporting COX-2 inhibition as a promising GBM therapy strategy. |
| format | Article |
| id | doaj-art-e604b81007774c5b9889d1d489f28557 |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj-art-e604b81007774c5b9889d1d489f285572025-08-20T02:17:19ZengMDPI AGAntioxidants2076-39212025-04-0114445910.3390/antiox14040459COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative StressFrancesca Rosaria Augello0Francesca Lombardi1Valeria Ciummo2Alessia Ciafarone3Maria Grazia Cifone4Benedetta Cinque5Paola Palumbo6Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, ItalyDepartment of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, ItalyDepartment of Innovative Technologies in Medicine and Dentistry, University “G. D’Annunzio”, 66100 Chieti, ItalyDepartment of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, ItalyDepartment of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, ItalyDepartment of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, ItalyDepartment of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, ItalyOxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activates antioxidant defenses, protecting GBM cells from therapy-induced oxidative stress and contributing to Temozolomide (TMZ) resistance. Cyclooxygenase-2 (COX-2) plays a key role in GBM chemoresistance by modulating the tumor microenvironment and supporting a pro-survival phenotype. The impact of COX-2 inhibition by celecoxib (CXB), a selective COX-2 inhibitor, combined with TMZ on oxidative stress modulation linked to resistance was investigated in GBM primary cultures and cell lines. The drug combination CXB+TMZ was tested on TMZ-sensitive and -resistant cells, and ROS levels and Nrf2 activation were evaluated via a DCFH-DA probe and Western blotting, respectively. The oxidative stress marker malondialdehyde and antioxidant enzymes were assayed using standard methods. COX-2 inhibition combined with TMZ significantly increased ROS, while TMZ alone induced a compensatory antioxidant response, sustaining resistance. Drug combination reduced this response, restoring oxidative stress even in TMZ-resistant cells. Prostaglandin E2 reversed these effects, confirming the role of the COX-2/PGE2 axis in redox balance. Drug combination increased ROS, disrupted redox homeostasis and overcame TMZ resistance, supporting COX-2 inhibition as a promising GBM therapy strategy.https://www.mdpi.com/2076-3921/14/4/459glioblastomatemozolomidecyclooxygenase-2inflammationoxidative stress |
| spellingShingle | Francesca Rosaria Augello Francesca Lombardi Valeria Ciummo Alessia Ciafarone Maria Grazia Cifone Benedetta Cinque Paola Palumbo COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress Antioxidants glioblastoma temozolomide cyclooxygenase-2 inflammation oxidative stress |
| title | COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress |
| title_full | COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress |
| title_fullStr | COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress |
| title_full_unstemmed | COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress |
| title_short | COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress |
| title_sort | cox 2 inhibition in glioblastoma cells counteracts resistance to temozolomide by inducing oxidative stress |
| topic | glioblastoma temozolomide cyclooxygenase-2 inflammation oxidative stress |
| url | https://www.mdpi.com/2076-3921/14/4/459 |
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