Auranofin inactivates phosphofructokinase in human neutrophils, leading to depletion of intracellular ATP and inhibition of superoxide generation and locomotion.
The effects of the oral gold compound auranofin (AF), at concentrations well within the therapeutic range (0.04-1.5 microM), on human neutrophil functions and energy metabolism were investigated in vitro. At the concentrations tested, this agent had minimal effects on neutrophil degranulation and phagocytosis. However, AF caused dose-related inhibition of neutrophil chemotaxis and stimulus-activated generation of superoxide, which was evident at concentrations as low as 0.04 microM. Inhibition of superoxide generation by activated neutrophils increased with the time of preincubation of the cells with AF at 37 degrees. At low concentrations of AF (less than 0.75 microM), early events (within 5 min) involved in the transduction, assembly, and activity of the neutrophil superoxide-generating enzyme NADPH oxidase appeared to be normal, but the cells were unable to sustain the level of oxygen consumption, superoxide production, and NADPH oxidase activity of the corresponding drug-free control cells. On a mechanistic level, coincubation of neutrophils with AF was associated with decreased glycolytic activity and depletion of intracellular ATP, apparently due to drug-mediated, dose-related inactivation of the glycolytic enzyme phosphofructokinase (PFK). Using purified PFK, the triethylphosphine gold (TEPG) moiety of AF, but not AF per se, caused dose-related inactivation of enzyme activity. These data indicate that the potent inhibition of neutrophil migration and reactive oxidant generation observed during treatment of neutrophils with low, therapeutically attainable concentrations of AF is related to TEPG-mediated inactivation of PFK and consequent interference with cellular energy metabolism and functions.
Anderson
R
R
Department of Immunology, University of Pretoria, Republic of South Africa.
Van Rensburg
C E
CE
Jooné
G K
GK
Lessing
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D001310:Auranofin / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009247:NADH, NADPH Oxidoreductases / Q000032:analysis; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010720:Phosphines; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors*; D013481:Superoxides / Q000378:metabolism*
D007773:Lactates; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010720:Phosphines; D013481:Superoxides; D019344:Lactic Acid; D001310:Auranofin; C016797:triethyl phosphine gold; D000255:Adenosine Triphosphate; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D010732:Phosphofructokinase-1