Senescence Under the Lens: X-ray vs. Proton Irradiation at Conventional and Ultra-High Dose Rate

Conventional radiotherapy based on X rays is used to treat more than 50% of cancers. Although effective, radiotherapy can damage healthy tissues around the tumor due to the X-ray dose deposition profile, as well as the safety margin needed to compensate for dose uncertainties. A notable side effect is cellular senescence, characterized by the cessation of cell division while maintaining metabolic activity and promoting the secretion of various components, called the senescence-associated secretory phenotype. To minimize toxicity in healthy tissues, proton therapy holds great promise as it enables tumors to be targeted more precisely while sparing healthy tissues beyond the tumor site. Another innovative method is ultra-high dose rate irradiation, which seems to induce less damage to healthy tissues while generating an anti-tumor response similar to standard dose rate irradiation. In this work, we aimed to compare the effects of X rays and protons at conventional dose rate (2 Gy/min) and ultra-high dose rate (454 Gy/s), on the induction of senescence in primary normal human dermal fibroblasts by analyzing several senescence biomarkers. Irradiation with ultra-high dose rate protons caused more pronounced cellular and nuclear morphological changes in normal human dermal fibroblasts than irradiation with conventional protons or X-rays. For other biomarkers, all three types of irradiations induced an increase in the proportion of senescence-associated beta-gal-positive cells, an irreversible cell cycle arrest and an accumulation of unrepaired DNA damage, but did not affect senescence-associated secretory phenotype.