Can radiation-induced apoptosis be modulated by inhibitors of energy metabolism?
OBJECTIVE
To determine the effect of the inhibitors of energy metabolism, 2-deoxyglucose (2DG) and sodium azide, on radiation-induced apoptosis.


METHODS
Radiation-induced apoptosis was determined in U937 monocytic leukaemia cells exposed to energy inhibitors post-irradiation. Apoptosis was scored microscopically using morphological criteria. Glycolysis was determined by assessing glucose consumption and lactate production. Adenine nucleotide levels were measured using a luciferase assay after enzymatic conversion to ATP. Respiration was measured using a Clark-type oxygen electrode.


RESULTS
In addition to their apoptosis-inducing properties, both 2DG and azide modified post-irradiation apoptosis. 2DG induced apoptotic radiosensitization after exposure to lower concentrations (5 mM, 10 mM) up to 20 h post-irradiation while a level of radioprotection was found after 5 h exposure to higher doses up to 100 mM. By contrast, all doses of azide examined (5-50 mM) induced apoptotic radioprotection at all times examined. Glycolytic flux and ATP levels fell rapidly with increasing 2DG dose but energy charge remained unchanged. Glycolysis was less influenced by azide, with ATP levels being initially maintained after exposure but decreasing in a dose-dependent manner at 3 h post-irradiation. However, energy charge was unaffected by azide at the concentrations examined.


CONCLUSIONS
Both 2DG and azide can influence radiation-induced apoptosis possibly through their effects on glycolysis and ATP levels. We suggest that modulation of energy metabolism provides mechanistic insight into radiation-induced apoptotic pathways.
Hunter
A J
AJ
Division of Radiation Oncology, Department of Radiation Medicine, University of Cape Town/Groote Schuur Hospital, Observatory, South Africa. Alistair@curie.uct.ac.za
Hendrikse
A S
AS
Renan
M J
MJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D003847:Deoxyglucose / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D011827:Radiation; D019810:Sodium Azide / Q000494:pharmacology; D013997:Time Factors; D020298:U937 Cells / Q000187:drug effects / Q000528:radiation effects
D004791:Enzyme Inhibitors; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D019810:Sodium Azide; D003847:Deoxyglucose; D008156:Luciferases; D005947:Glucose