Ionizing radiation causes DNA damage and consequent apoptosis, mainly due to the production of hydroxyl radicals (HO•) that follows radiolytic splitting of water. However, superoxide (O2•−) and H2O2 also form and induce oxidative stress with resulting LMP (lysosomal membrane permeabilization) arising from iron-catalysed oxidative events. The latter will contribute significantly to radiation-induced cell death and its degree largely depends on the quantities of lysosomal redox-active iron present as a consequence of autophagy and endocytosis of iron-rich compounds. Therefore radiation sensitivity might be depressed by lysosome-targeted iron chelators. In the present study, we have shown that cells in culture are significantly protected from ionizing radiation damage if initially exposed to the lipophilic iron chelator SIH (salicylaldehyde isonicotinoyl hydrazone), and that this effect is based on SIH-dependent lysosomal stabilization against oxidative stress. According to its dose-response-modifying effect, SIH is a most powerful radioprotector and a promising candidate for clinical application, mainly to reduce the radiation sensitivity of normal tissue. We propose, as an example, that inhalation of SIH before each irradiation session by patients undergoing treatment for lung malignancies would protect normally aerated lung tissue against life-threatening pulmonary fibrosis, whereas the sensitivity of malignant lung tumours, which usually are non-aerated, will not be affected by inhaled SIH.
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December 2010
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Research Article|
November 12 2010
Chelation of lysosomal iron protects against ionizing radiation
Carsten Berndt;
*Division for Biochemistry, Department for Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden
†Institute for Clinical Cytobiology and Cytopathology, Philipps-Universität, 35037 Marburg, Germany
2To whom correspondence should be addressed (email Carsten.Berndt@ki.se).
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Tino Kurz;
Tino Kurz
1
‡Division of Pharmacology, Faculty of Health Sciences, Linköping University 581 85 Linköping, Sweden
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Markus Selenius;
Markus Selenius
§Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, 141 86 Stockholm, Sweden
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Aristi P. Fernandes;
Aristi P. Fernandes
§Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, 141 86 Stockholm, Sweden
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Margareta R. Edgren;
Margareta R. Edgren
∥Division of Medical Radiation Physics, Department of Oncology-Pathology, Karolinska Institute, 171 76 Stockholm, Sweden
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Ulf T. Brunk
Ulf T. Brunk
‡Division of Pharmacology, Faculty of Health Sciences, Linköping University 581 85 Linköping, Sweden
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Publisher: Portland Press Ltd
Received:
July 07 2010
Revision Received:
September 14 2010
Accepted:
September 16 2010
Accepted Manuscript online:
September 16 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 432 (2): 295–301.
Article history
Received:
July 07 2010
Revision Received:
September 14 2010
Accepted:
September 16 2010
Accepted Manuscript online:
September 16 2010
Citation
Carsten Berndt, Tino Kurz, Markus Selenius, Aristi P. Fernandes, Margareta R. Edgren, Ulf T. Brunk; Chelation of lysosomal iron protects against ionizing radiation. Biochem J 1 December 2010; 432 (2): 295–301. doi: https://doi.org/10.1042/BJ20100996
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