title: 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 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.
authors: Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors: Michael I
authors: MI
authors: Koukourakis
authors: Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors: Alexandra
authors: A
authors: Giatromanolaki
authors: Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.|Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors: Christos E
authors: CE
authors: Zois
authors: Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors: Dimitra
authors: D
authors: Kalamida
authors: Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors: Stamatia
authors: S
authors: Pouliliou
authors: Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors: Ilias V
authors: IV
authors: Karagounis
authors: The Chemistry Research laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
authors: Tzu-Lan
authors: TL
authors: Yeh
authors: The Chemistry Research laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
authors: Martine I
authors: MI
authors: Abboud
authors: The Chemistry Research laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
authors: Timothy D W
authors: TD
authors: Claridge
authors: The Chemistry Research laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
authors: Christopher J
authors: CJ
authors: Schofield
authors: Department of Pathology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
authors: Efthimios
authors: E
authors: Sivridis
authors: Laboratory of Experimental Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
authors: Costantinos
authors: C
authors: Simopoulos
authors: Department of Physical Education and Sports Science. Democritus University of Thrace, Komotini, Greece.
authors: Savvas P
authors: SP
authors: Tokmakidis
authors: Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors: Adrian L
authors: AL
authors: Harris
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000528:radiation effects; D022781:Hepatocytes / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011837:Radiation-Protective Agents / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011837:Radiation-Protective Agents; C495682:Slc2a2 protein, mouse; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D004999:Amifostine; D010100:Oxygen