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PLoS One. 2017 Aug 3;12(8):e0182508. doi: 10.1371/journal.pone.0182508. eCollection 2017.

Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress.

Author information

1
Department of Radiation Oncology (MaastRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
2
Department of Clinical Genomics, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
3
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
4
Department of Toxicology, NUTRIM - School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
5
Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
6
Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.

Abstract

Several clinically used drugs are mitotoxic causing mitochondrial DNA (mtDNA) variations, and thereby influence cancer treatment response. We hypothesized that radiation responsiveness will be enhanced in cellular models with decreased mtDNA content, attributed to altered reactive oxygen species (ROS) production and antioxidant capacity. For this purpose BEAS-2B, A549, and 143B cell lines were depleted from their mtDNA (ρ0). Overall survival after irradiation was increased (p<0.001) for BEAS-2B ρ0 cells, while decreased for both tumor ρ0 lines (p<0.05). In agreement, increased residual DNA damage was observed after mtDNA depletion for A549 and 143B cells. Intrinsic radiosensitivity (surviving fraction at 2Gy) was not influenced. We investigated whether ROS levels, oxidative stress and/or antioxidant responses were responsible for altered radiation responses. Baseline ROS formation was similar between BEAS-2B parental and ρ0 cells, while reduced in A549 and 143B ρ0 cells, compared to their parental counterparts. After irradiation, ROS levels significantly increased for all parental cell lines, while levels for ρ0 cells remained unchanged. In order to investigate the presence of oxidative stress upon irradiation reduced glutathione: oxidized glutathione (GSH:GSSG) ratios were determined. Irradiation reduced GSH:GSSG ratios for BEAS-2B parental and 143B ρ0, while for A549 this ratio remained equal. Additionally, changes in antioxidant responses were observed. Our results indicate that mtDNA depletion results in varying radiation responses potentially involving variations in cellular ROS and antioxidant defence mechanisms. We therefore suggest when mitotoxic drugs are combined with radiation, in particular at high dose per fraction, the effect of these drugs on mtDNA copy number should be explored.

PMID:
28771582
PMCID:
PMC5542624
DOI:
10.1371/journal.pone.0182508
[Indexed for MEDLINE]
Free PMC Article

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