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Mitochondrial Responses to Conventional and Ultra-high Dose Rate (FLASH) Radiation
Emily G Caggiano1, Maryam E Elizondo1, Alan Lopez Hernandez1
1Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
FLASH radiation therapy (RT) spares mitochondria in normal cells but not cancer cells, potentially explaining reduced toxicity. This finding offers insights into improving radiation treatment outcomes.
Area of Science:
- Oncology
- Radiation Biology
- Cellular Biology
Background:
- Ultra-high dose rate (FLASH) radiation therapy (RT) shows promise for reducing normal tissue toxicity compared to conventional dose rate (CONV) RT.
- The underlying mechanisms of the FLASH effect, particularly concerning normal tissue protection, remain largely unknown.
- Mitochondrial integrity is crucial for cellular health and function, and its preservation may be key to mitigating radiation-induced damage.
Purpose of the Study:
- To investigate the hypothesis that FLASH RT preserves mitochondrial integrity in nontumorigenic cells, contributing to reduced normal tissue toxicity.
- To elucidate the mechanisms behind the protective effects of FLASH RT by examining mitochondrial health and function.
- To compare the impact of FLASH and CONV RT on both cancer cells and normal cells in vitro, ex vivo, and in vivo.
Main Methods:
- Assessed mitochondrial health and function using assays for metabolic flux, membrane potential, reactive oxygen species (ROS), DNA damage, and copy number.
- Examined mitochondrial morphology and cellular responses in murine pancreatic cancer (PDAC) cells and nontumorigenic pancreatic cells.
- Evaluated tumor growth delay and animal survival in mice bearing subcutaneous KPC tumors treated with FLASH and CONV RT.
Main Results:
- In vitro and ex vivo studies showed that FLASH RT caused similar mitochondrial damage in PDAC cells as CONV RT, but spared nontumorigenic cells.
- In vivo experiments demonstrated comparable tumor growth delay between FLASH and CONV RT groups.
- Longer survival in the FLASH-treated group was attributed to reduced normal tissue toxicity rather than enhanced tumor control.
Conclusions:
- FLASH RT selectively preserves mitochondrial function in nontumorigenic cells compared to CONV RT.
- This selective mitochondrial sparing in normal tissues is a potential key mechanism driving the reduced toxicity observed with FLASH RT.
- Further research into mitochondrial protection mechanisms could optimize FLASH RT protocols for improved cancer treatment outcomes.
