Normal tissue radioprotection by amifostine via Warburg-type effects
Abstract The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen con...
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Nature Portfolio
2016-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/srep30986 |
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| author | Michael I. Koukourakis Alexandra Giatromanolaki Christos E. Zois Dimitra Kalamida Stamatia Pouliliou Ilias V. Karagounis Tzu-Lan Yeh Martine I. Abboud Timothy D. W. Claridge Christopher J. Schofield Efthimios Sivridis Costantinos Simopoulos Savvas P. Tokmakidis Adrian L. Harris |
| author_facet | Michael I. Koukourakis Alexandra Giatromanolaki Christos E. Zois Dimitra Kalamida Stamatia Pouliliou Ilias V. Karagounis Tzu-Lan Yeh Martine I. Abboud Timothy D. W. Claridge Christopher J. Schofield Efthimios Sivridis Costantinos Simopoulos Savvas P. Tokmakidis Adrian L. Harris |
| author_sort | Michael I. Koukourakis |
| collection | DOAJ |
| description | Abstract The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although amifostine in vitro did not inhibit the activity of the prolyl-hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1α, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer. |
| format | Article |
| id | doaj-art-c69a6c00eac843e78e856d126f0b005f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2016-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-c69a6c00eac843e78e856d126f0b005f2025-02-02T12:25:45ZengNature PortfolioScientific Reports2045-23222016-08-016111410.1038/srep30986Normal tissue radioprotection by amifostine via Warburg-type effectsMichael I. Koukourakis0Alexandra Giatromanolaki1Christos E. Zois2Dimitra Kalamida3Stamatia Pouliliou4Ilias V. Karagounis5Tzu-Lan Yeh6Martine I. Abboud7Timothy D. W. Claridge8Christopher J. Schofield9Efthimios Sivridis10Costantinos Simopoulos11Savvas P. Tokmakidis12Adrian L. Harris13Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, GreeceDepartment of Pathology, Democritus University of Thrace, Alexandroupolis 68100, GreeceDepartment of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, GreeceDepartment of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, GreeceDepartment of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, GreeceDepartment of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, GreeceThe Chemistry Research laboratoryThe Chemistry Research laboratoryThe Chemistry Research laboratoryThe Chemistry Research laboratoryDepartment of Pathology, Democritus University of Thrace, Alexandroupolis 68100, GreeceLaboratory of Experimental Surgery, University Hospital of Alexandroupolis, Democritus University of ThraceDepartment of Physical Education and Sports Science. Democritus University of ThraceCancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of OxfordAbstract The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although amifostine in vitro did not inhibit the activity of the prolyl-hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1α, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer.https://doi.org/10.1038/srep30986 |
| spellingShingle | Michael I. Koukourakis Alexandra Giatromanolaki Christos E. Zois Dimitra Kalamida Stamatia Pouliliou Ilias V. Karagounis Tzu-Lan Yeh Martine I. Abboud Timothy D. W. Claridge Christopher J. Schofield Efthimios Sivridis Costantinos Simopoulos Savvas P. Tokmakidis Adrian L. Harris Normal tissue radioprotection by amifostine via Warburg-type effects Scientific Reports |
| title | Normal tissue radioprotection by amifostine via Warburg-type effects |
| title_full | Normal tissue radioprotection by amifostine via Warburg-type effects |
| title_fullStr | Normal tissue radioprotection by amifostine via Warburg-type effects |
| title_full_unstemmed | Normal tissue radioprotection by amifostine via Warburg-type effects |
| title_short | Normal tissue radioprotection by amifostine via Warburg-type effects |
| title_sort | normal tissue radioprotection by amifostine via warburg type effects |
| url | https://doi.org/10.1038/srep30986 |
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