Speaker
Descrizione
FLASH radiotherapy (FLASH-RT) delivers radiation at ultra-high dose rates (UHDRs), achieving strong antitumor efficacy while minimizing normal tissue toxicity. However, the cellular and metabolic mechanisms underlying this ‘FLASH effect’ remain unclear. Here, we compared the impact of FLASH versus conventional (CONV) irradiation (8 Gy in vitro) in glioma GL261 cells and healthy primary glial cultures. Multiparameters, including cytotoxicity, oxidative stress, mitochondrial function, and bioenergetics were evaluated through real-time population-based assays, flow cytometry, Seahorse analysis, and gene expression profiling. In healthy glial cells, FLASH-RT markedly attenuated ROS accumulation, preserved mitochondrial membrane potential and respiration, and maintained viability, while CONV-RT induced sustained oxidative stress and mitochondrial dysfunction. FLASH-treated glial cells showed transcriptional signatures of cell cycle arrest and senescence rather than apoptosis, indicating activation of repair and survival pathways. In contrast, FLASH-RT in tumor cells enhanced ROS production, mitochondrial depolarization, and metabolic impairment, leading to pronounced cell death and early activation of autophagy-related genes. Both modalities reduced glioma cell viability by 72 h, but only FLASH preserved mitochondrial integrity in non-tumoral cells. Pharmacological inhibition of PARP, calpains, and necroptosis further revealed that CONV-RT–induced metabolic collapse is primarily PARP- and necroptosis-dependent, whereas FLASH-RT triggers a more distributed and modulable stress response, with glial cells showing minimal inhibitor sensitivity and GL261 cells exhibiting multimodal vulnerability. These findings demonstrate, for the first time, how FLASH-RT reprograms a cell-type-specific metabolism that spares healthy cells while promoting glioma cell death, providing a mechanistic basis for its therapeutic advantage and supporting its further development as a next-generation radiotherapy approach.
