Impact of Ferroptosis Inducers on Chronic Radiation-exposed Survivor Glioblastoma Cells

Introduction: The median survival of patients diagnosed with glioblastoma is very poor, despite efforts to improve the therapeutic effects of surgery, followed by treatment with temozolomide (TMZ) and ionizing radiation (IR). The utilization of TMZ or IR survivor cell models has enhanced the understanding of glioblastoma biology and the development of novel therapeutic strategies. In this present study, naïve U373 and clinically relevant U373 IRsurvivor (Surv) cells were used, as the IR-Surv cell model mimics the chronic long-term exposure to standardized radiotherapy for patients with glioblastoma in the clinic. As the role of ferroptosis in the IR survivor cell model has not previously been reported, we aimed to clarify its involvement in the clinically relevant IR-Surv glioblastoma model Methods: Transcriptomic alterations of ferroptosis-related genes were studied on naïve U373 and IR-Surv cell populations. To determine the effects of glutathione peroxidase inhibitors, ferroptosis-inducing agent 56 (FIN56) and Ras synthetic lethal 3 (RSL3), on the cells, several properties were assessed, including colony formation, cell viability and lipid peroxidation. Results: Results from the transcriptomic analysis identified ferroptosis as a critical mechanism after radiation exposure in glioblastoma. Our findings also identified the role of ferroptosis inducers (FINs) in IR-survivor cells and suggested using FINs to treat glioblastoma. Conclusion: FINs serve an important role in radioresistant cells; thus, the results of the present study may contribute to improving survival in patients with glioblastoma.