Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress.
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 (RO...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5542624?pdf=render |
| _version_ | 1818027630128005120 |
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| author | Marike W van Gisbergen An M Voets Rianne Biemans Roland F Hoffmann Marie-José Drittij-Reijnders Guido R M M Haenen Irene H Heijink Kasper M A Rouschop Ludwig J Dubois Philippe Lambin |
| author_facet | Marike W van Gisbergen An M Voets Rianne Biemans Roland F Hoffmann Marie-José Drittij-Reijnders Guido R M M Haenen Irene H Heijink Kasper M A Rouschop Ludwig J Dubois Philippe Lambin |
| author_sort | Marike W van Gisbergen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T04:50:57Z |
| format | Article |
| id | doaj.art-462e516ed1d64c4bab3f328b4dc83585 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T04:50:57Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-462e516ed1d64c4bab3f328b4dc835852022-12-22T02:01:37ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018250810.1371/journal.pone.0182508Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress.Marike W van GisbergenAn M VoetsRianne BiemansRoland F HoffmannMarie-José Drittij-ReijndersGuido R M M HaenenIrene H HeijinkKasper M A RouschopLudwig J DuboisPhilippe LambinSeveral 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.http://europepmc.org/articles/PMC5542624?pdf=render |
| spellingShingle | Marike W van Gisbergen An M Voets Rianne Biemans Roland F Hoffmann Marie-José Drittij-Reijnders Guido R M M Haenen Irene H Heijink Kasper M A Rouschop Ludwig J Dubois Philippe Lambin Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress. PLoS ONE |
| title | Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress. |
| title_full | Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress. |
| title_fullStr | Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress. |
| title_full_unstemmed | Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress. |
| title_short | Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress. |
| title_sort | distinct radiation responses after in vitro mtdna depletion are potentially related to oxidative stress |
| url | http://europepmc.org/articles/PMC5542624?pdf=render |
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