The Intrinsic Significance of Proton FLASH-Mediated Sparing Effect On Benign Pancreatic Cells
Y Lee1, 2 *, (1) Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, TW. (2) Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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PO-GePV-M-352 (Sunday, 7/10/2022) [Eastern Time (GMT-4)]
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Purpose: To understand the biophysical mechanism of FLASH radiation-mediated sparing effect as the differential biophysical mechanisms for explaining the preferentially sparing effect on healthy tissues are not clear.
Methods: Single doses of proton irradiation of hTERT-HPNE cells was carried out with 96-well plates at dose rates of 100.0 Gy/s and 0.2 Gy/s, separately. Assays of Cell Counting Kit-8, colony formation and cytotoxicity were performed for assessing bioeffects from the administration with IACS-010759 and/ or proton irradiation. Assessments of mitochondrial ROS (reactive oxygen species) and oxidative DNA damage along with the expression of phase I and phase II enzymes were also conducted after irradiation.
Results: Ultrahigh dose rate of protons induced less killing effect (with an average surviving fraction five times higher than that resulting from the proton dose delivered at 0.2 Gy/s) and cytotoxicity (at a 1.44-fold overall regressional reduction rate of the group irradiated at 0.2 Gy/s) on benign HPNE cells. Irradiation of HPNE cells with ultrahigh dose rate of protons resulted in significant reduction of mitochondrial oxidative stress (at the reduction rate of around 0.34) in association with mitochondrial oxidative metabolism (indicated by a 1.33-fold increase in cytochrome c oxidase subunit 1 expression). OXPHOS inhibition on HPNE cells abolished mitochondrial redox control enacted by proton FLASH (indicated by an overall 3.53-fold increase of MitoTracker Red oxidation), leading to upregulation of nuclear oxidative stress (evidenced by an overall 13.60-fold increase of dihydroethidium oxidation).
Conclusion: From this study, proton FLASH was found to enhance mitochondrial oxidative metabolism, which mitigated proton irradiation-induced mitochondrial ROS and oxidative DNA damage. This indicates that proton FLASH, compared with proton irradiation at the dose rate of 0.02 Gy/s, at least partially spares benign pancreatic cells by the reduction of radiation-induced indirect effect.
Funding Support, Disclosures, and Conflict of Interest: This work was supported by a grant from The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology
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