Enhancing Therapeutic Approaches in Glioblastoma with Pro-Oxidant Treatments and Synergistic Combinations: In Vitro Experience of Doxorubicin and Photodynamic Therapy

Abstract

Glioblastoma (GBM) is an aggressive brain cancer characterized by significant molecularand cellular heterogeneity, which complicates treatment efforts. Current standard therapies, includingsurgical resection, radiation, and temozolomide (TMZ) chemotherapy, often fail to achieve longtermremission due to tumor recurrence and resistance. A pro-oxidant environment is involvedin glioma progression, with oxidative stress contributing to the genetic instability that leads togliomagenesis. Evaluating pro-oxidant therapies in brain tumors is crucial due to their potential toselectively target and eradicate cancer cells by exploiting the elevated oxidative stress levels inherentin these malignant cells, thereby offering a novel and effective strategy for overcoming resistance toconventional therapies. This study investigates the therapeutic potential of doxorubicin (DOX) andphotodynamic therapy (PDT) with Me-ALA, focusing on their effects on redox homeostasis. BasalROS levels and antioxidant gene expression (NFE2L2, CAT, GSR) were quantitatively assessed acrossGBM cell lines, revealing significant variability probably linked to genetic differences. DOX andPDT treatments, both individually and in combination, were analyzed for their efficacy in inducingoxidative stress and cytotoxicity. An in silico analysis further explored the relationship between genemutations and oxidative stress in GBM patients, providing insights into the molecular mechanismsunderlying treatment responses. Our findings suggest that pro-oxidant therapies, such as DOXand PDT in combination, could selectively target GBM cells, highlighting a promising avenue forimproving therapeutic outcomes in GBM.