Combinatorial effect of epirubicin and 5-fluorouracil in the treatment of temozolomide-resistant glioblastoma cells

Background: Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by rapid proliferation and invasiveness. It is associated with a poor prognosis due to acquired resistance to temozolomide (TMZ). In this study, we investigated whether a combination of epirubicin, 5-fluorouracil (5-FU), and TMZ could improve TMZ sensitivity in resistant GBM cells and help overcome resistance. Materials and methods: TMZ resistance was established in the U87MG cell line. The MTT assay was used to measure cell viability. Reactive oxygen species (ROS) and apoptosis were measured using flow cytometry. RNA-seq was used to evaluate genomic changes based on treatment with drugs alone or in combination. Results: We demonstrated that the triple-drug combination significantly reduced cell viability. The biochemical pathways involved revealed that this combination therapy significantly increased the generation of ROS. The RNA-seq analysis indicated that combination therapy effectively suppressed cell cycle regulatory pathways, enhancing cell cycle arrest and promoting apoptosis in TMZ-resistant cells. Conclusion: These findings underscore the potential viability of integrating epirubicin and 5-FU with TMZ to improve therapeutic outcomes in patients suffering from chemoresistant GBM. These combination therapies could represent an important advance in the treatment of this challenging malignancy.