Radiation and chemotherapy bystander effects induce early genomic instability events: telomere shortening and bridge formation coupled with mitochondrial dysfunction.

Hdl Handle:
http://hdl.handle.net/10147/207497
Title:
Radiation and chemotherapy bystander effects induce early genomic instability events: telomere shortening and bridge formation coupled with mitochondrial dysfunction.
Authors:
Gorman, Sheeona; Tosetto, Miriam; Lyng, Fiona; Howe, Orla; Sheahan, Kieran; O'Donoghue, Diarmuid; Hyland, John; Mulcahy, Hugh; O'Sullivan, Jacintha
Affiliation:
Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park,, Dublin 4, Ireland.
Citation:
Mutat Res. 2009 Oct 2;669(1-2):131-8. Epub 2009 Jun 18.
Journal:
Mutation research
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207497
DOI:
10.1016/j.mrfmmm.2009.06.003
PubMed ID:
19540247
Abstract:
The bridge breakage fusion cycle is a chromosomal instability mechanism responsible for genomic changes. Radiation bystander effects induce genomic instability; however, the mechanism driving this instability is unknown. We examined if radiation and chemotherapy bystander effects induce early genomic instability events such as telomere shortening and bridge formation using a human colon cancer explant model. We assessed telomere lengths, bridge formations, mitochondrial membrane potential and levels of reactive oxygen species in bystander cells exposed to medium from irradiated and chemotherapy-treated explant tissues. Bystander cells exposed to media from 2Gy, 5Gy, FOLFOX treated tumor and matching normal tissue showed a significant reduction in telomere lengths (all p values <0.018) and an increase in bridge formations (all p values <0.017) compared to bystander cells treated with media from unirradiated tissue (0Gy) at 24h. There was no significant difference between 2Gy and 5Gy treatments, or between effects elicited by tumor versus matched normal tissue. Bystander cells exposed to media from 2Gy irradiated tumor tissue showed significant depolarisation of the mitochondrial membrane potential (p=0.012) and an increase in reactive oxygen species levels. We also used bystander cells overexpressing a mitochondrial antioxidant manganese superoxide dismutase (MnSOD) to examine if this antioxidant could rescue the mitochondrial changes and subsequently influence nuclear instability events. In MnSOD cells, ROS levels were reduced (p=0.02) and mitochondrial membrane potential increased (p=0.04). These events were coupled with a decrease in percentage of cells with anaphase bridges and a decrease in the number of cells undergoing telomere length shortening (p values 0.01 and 0.028 respectively). We demonstrate that radiation and chemotherapy bystander responses induce early genomic instability coupled with defects in mitochondrial function. Restoring mitochondrial function through overexpression of MnSOD significantly rescues nuclear instability events; anaphase bridges and telomere length shortening.
Language:
eng
MeSH:
Aged; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; *Bystander Effect; Colorectal Neoplasms/drug therapy/*genetics/radiotherapy; Combined Modality Therapy; Female; Fluorouracil/therapeutic use; *Genomic Instability; Humans; Leucovorin/therapeutic use; Male; Membrane Potential, Mitochondrial; Mitochondrial Diseases/*metabolism; Organoplatinum Compounds/therapeutic use; Oxidative Stress; Prognosis; Radiotherapy Dosage; Reactive Oxygen Species/metabolism; Superoxide Dismutase/metabolism; Telomere/*genetics/metabolism; Tissue Culture Techniques; Tissue Extracts; Treatment Outcome
ISSN:
0027-5107 (Print); 0027-5107 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorGorman, Sheeonaen_GB
dc.contributor.authorTosetto, Miriamen_GB
dc.contributor.authorLyng, Fionaen_GB
dc.contributor.authorHowe, Orlaen_GB
dc.contributor.authorSheahan, Kieranen_GB
dc.contributor.authorO'Donoghue, Diarmuiden_GB
dc.contributor.authorHyland, Johnen_GB
dc.contributor.authorMulcahy, Hughen_GB
dc.contributor.authorO'Sullivan, Jacinthaen_GB
dc.date.accessioned2012-02-01T10:29:31Z-
dc.date.available2012-02-01T10:29:31Z-
dc.date.issued2012-02-01T10:29:31Z-
dc.identifier.citationMutat Res. 2009 Oct 2;669(1-2):131-8. Epub 2009 Jun 18.en_GB
dc.identifier.issn0027-5107 (Print)en_GB
dc.identifier.issn0027-5107 (Linking)en_GB
dc.identifier.pmid19540247en_GB
dc.identifier.doi10.1016/j.mrfmmm.2009.06.003en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207497-
dc.description.abstractThe bridge breakage fusion cycle is a chromosomal instability mechanism responsible for genomic changes. Radiation bystander effects induce genomic instability; however, the mechanism driving this instability is unknown. We examined if radiation and chemotherapy bystander effects induce early genomic instability events such as telomere shortening and bridge formation using a human colon cancer explant model. We assessed telomere lengths, bridge formations, mitochondrial membrane potential and levels of reactive oxygen species in bystander cells exposed to medium from irradiated and chemotherapy-treated explant tissues. Bystander cells exposed to media from 2Gy, 5Gy, FOLFOX treated tumor and matching normal tissue showed a significant reduction in telomere lengths (all p values <0.018) and an increase in bridge formations (all p values <0.017) compared to bystander cells treated with media from unirradiated tissue (0Gy) at 24h. There was no significant difference between 2Gy and 5Gy treatments, or between effects elicited by tumor versus matched normal tissue. Bystander cells exposed to media from 2Gy irradiated tumor tissue showed significant depolarisation of the mitochondrial membrane potential (p=0.012) and an increase in reactive oxygen species levels. We also used bystander cells overexpressing a mitochondrial antioxidant manganese superoxide dismutase (MnSOD) to examine if this antioxidant could rescue the mitochondrial changes and subsequently influence nuclear instability events. In MnSOD cells, ROS levels were reduced (p=0.02) and mitochondrial membrane potential increased (p=0.04). These events were coupled with a decrease in percentage of cells with anaphase bridges and a decrease in the number of cells undergoing telomere length shortening (p values 0.01 and 0.028 respectively). We demonstrate that radiation and chemotherapy bystander responses induce early genomic instability coupled with defects in mitochondrial function. Restoring mitochondrial function through overexpression of MnSOD significantly rescues nuclear instability events; anaphase bridges and telomere length shortening.en_GB
dc.language.isoengen_GB
dc.subject.meshAgeden_GB
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols/therapeutic useen_GB
dc.subject.mesh*Bystander Effecten_GB
dc.subject.meshColorectal Neoplasms/drug therapy/*genetics/radiotherapyen_GB
dc.subject.meshCombined Modality Therapyen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshFluorouracil/therapeutic useen_GB
dc.subject.mesh*Genomic Instabilityen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLeucovorin/therapeutic useen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMembrane Potential, Mitochondrialen_GB
dc.subject.meshMitochondrial Diseases/*metabolismen_GB
dc.subject.meshOrganoplatinum Compounds/therapeutic useen_GB
dc.subject.meshOxidative Stressen_GB
dc.subject.meshPrognosisen_GB
dc.subject.meshRadiotherapy Dosageen_GB
dc.subject.meshReactive Oxygen Species/metabolismen_GB
dc.subject.meshSuperoxide Dismutase/metabolismen_GB
dc.subject.meshTelomere/*genetics/metabolismen_GB
dc.subject.meshTissue Culture Techniquesen_GB
dc.subject.meshTissue Extractsen_GB
dc.subject.meshTreatment Outcomeen_GB
dc.titleRadiation and chemotherapy bystander effects induce early genomic instability events: telomere shortening and bridge formation coupled with mitochondrial dysfunction.en_GB
dc.contributor.departmentCentre for Colorectal Disease, St. Vincent's University Hospital, Elm Park,, Dublin 4, Ireland.en_GB
dc.identifier.journalMutation researchen_GB
dc.description.provinceLeinster-

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