Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.

Hdl Handle:
http://hdl.handle.net/10147/200970
Title:
Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.
Authors:
Anoopkumar-Dukie, S; Conere, T; Sisk, G D; Allshire, A
Affiliation:
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
Citation:
Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines. 2009, 82 (982):847-54 Br J Radiol
Journal:
The British journal of radiology
Issue Date:
Oct-2009
URI:
http://hdl.handle.net/10147/200970
DOI:
10.1259/bjr/35746067
PubMed ID:
19366737
Additional Links:
http://bjr.birjournals.org/content/82/982/847.full.pdf+html
Abstract:
Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.
Item Type:
Article
Language:
en
Description:
Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.
MeSH:
Anti-Bacterial Agents; Bongkrekic Acid; Breast Neoplasms; Cell Line, Tumor; Cyclosporine; Female; Humans; Immunosuppressive Agents; Melanoma; Mitochondria; Oxidative Stress; Radiation Tolerance; Tacrolimus; Uterine Cervical Neoplasms; bcl-2-Associated X Protein
ISSN:
1748-880X

Full metadata record

DC FieldValue Language
dc.contributor.authorAnoopkumar-Dukie, Sen
dc.contributor.authorConere, Ten
dc.contributor.authorSisk, G Den
dc.contributor.authorAllshire, Aen
dc.date.accessioned2012-01-09T15:50:11Z-
dc.date.available2012-01-09T15:50:11Z-
dc.date.issued2009-10-
dc.identifier.citationMitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines. 2009, 82 (982):847-54 Br J Radiolen
dc.identifier.issn1748-880X-
dc.identifier.pmid19366737-
dc.identifier.doi10.1259/bjr/35746067-
dc.identifier.urihttp://hdl.handle.net/10147/200970-
dc.descriptionOxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.en
dc.description.abstractOxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.-
dc.language.isoenen
dc.relation.urlhttp://bjr.birjournals.org/content/82/982/847.full.pdf+htmlen
dc.subject.meshAnti-Bacterial Agents-
dc.subject.meshBongkrekic Acid-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCyclosporine-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshImmunosuppressive Agents-
dc.subject.meshMelanoma-
dc.subject.meshMitochondria-
dc.subject.meshOxidative Stress-
dc.subject.meshRadiation Tolerance-
dc.subject.meshTacrolimus-
dc.subject.meshUterine Cervical Neoplasms-
dc.subject.meshbcl-2-Associated X Protein-
dc.titleMitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.en
dc.identifier.journalThe British journal of radiologyen
dc.description.provinceMunster-

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