Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.
Affiliation
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.Issue Date
2009-10MeSH
Anti-Bacterial AgentsBongkrekic 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
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Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines. 2009, 82 (982):847-54 Br J RadiolJournal
The British journal of radiologyDOI
10.1259/bjr/35746067PubMed ID
19366737Additional Links
http://bjr.birjournals.org/content/82/982/847.full.pdf+htmlAbstract
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
ArticleLanguage
enISSN
1748-880Xae974a485f413a2113503eed53cd6c53
10.1259/bjr/35746067
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