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

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    Authors
    Anoopkumar-Dukie, S
    Conere, T
    Sisk, G D
    Allshire, A
    Affiliation
    Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
    Issue Date
    2009-10
    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
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    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
    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
    ISSN
    1748-880X
    ae974a485f413a2113503eed53cd6c53
    10.1259/bjr/35746067
    Scopus Count
    Collections
    Cork University Hospital

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