The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO·) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce ‘reparative autophagocytosis’, causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy radiation dose increased the ‘loose’ iron content of the (still viable) cells approx. 5-fold when assayed 24 h later. Cytochemical staining revealed that most redox-active iron was within the lysosomes. The increase of intralysosomal iron was associated with ‘reparative autophagocytosis’, and sensitized cells to lysosomal rupture and consequent apoptotic/necrotic death following a second, much lower dose of radiation (20 Gy) 24 h after the first one. A high-molecular-mass derivative of desferrioxamine, which specifically localizes intralysosomally following endocytic uptake, added to the culture medium before either the first or the second dose of radiation, stabilized lysosomes and largely prevented cell death. These observations may provide a biological rationale for fractionated radiation.
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Research Article|
July 26 2005
Radiation-induced cell death: importance of lysosomal destabilization
H. Lennart Persson;
H. Lennart Persson
1
*Division of Pulmonary Medicine, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden
†Division of Pathology II, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden
1To whom correspondence should be addressed (email Lenpe@inr.liu.se).
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Tino Kurz;
Tino Kurz
‡Division of Pharmacology, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden
§Henry Wellcome Laboratory for Biogerontology Research, University of Newcastle upon Tyne, Newcastle upon Tyne NE4 6BE, U.K.
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John W. Eaton;
John W. Eaton
‡Division of Pharmacology, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden
∥James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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Ulf T. Brunk
Ulf T. Brunk
‡Division of Pharmacology, Faculty of Health Sciences, University of Linköping, SE-581 85 Linköping, Sweden
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Publisher: Portland Press Ltd
Received:
February 11 2005
Revision Received:
March 29 2005
Accepted:
April 06 2005
Accepted Manuscript online:
April 06 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 389 (3): 877–884.
Article history
Received:
February 11 2005
Revision Received:
March 29 2005
Accepted:
April 06 2005
Accepted Manuscript online:
April 06 2005
Citation
H. Lennart Persson, Tino Kurz, John W. Eaton, Ulf T. Brunk; Radiation-induced cell death: importance of lysosomal destabilization. Biochem J 1 August 2005; 389 (3): 877–884. doi: https://doi.org/10.1042/BJ20050271
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