Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines
| Autor: | T. Conere, Ashley Allshire, Garry D. Sisk, Shailendra Anoopkumar-Dukie |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cell
Uterine Cervical Neoplasms Breast Neoplasms Mitochondrion Radiation Tolerance Tacrolimus HeLa Adenine nucleotide Cell Line Tumor Cyclosporin a medicine Humans Radiology Nuclear Medicine and imaging Radiosensitivity Melanoma bcl-2-Associated X Protein biology Kinase Chemistry General Medicine biology.organism_classification Anti-Bacterial Agents Mitochondria Oxidative Stress medicine.anatomical_structure Mitochondrial permeability transition pore Immunology Cyclosporine Cancer research Female Bongkrekic Acid Immunosuppressive Agents |
| Zdroj: | The British Journal of Radiology. 82:847-854 |
| ISSN: | 1748-880X 0007-1285 |
| DOI: | 10.1259/bjr/35746067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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