Nitroxide TEMPOL impairs mitochondrial function and induces apoptosis in HL60 cells.
The piperidine nitroxide TEMPOL induces apoptosis in a number of tumor cell lines through free radical-dependent mechanisms. As mitochondria play a major role in apoptosis as both source and target for free radicals, the present study focuses on mitochondrial effects of TEMPOL in a human promyelocytic leukemic cell line (HL-60). On 24-h exposure to TEMPOL, the following alterations were observed: 1) decrease in both the intracellular and mitochondrial glutathione pools; 2) impairment of oxidative phosphorylation; and 3) decrease in mitochondrial membrane potential. In addition, TEMPOL was found to specifically target complex I of the respiratory chain, with minor effects on complexes II and IV, suggesting that mitochondrial effects might play a role in TEMPOL-induced oxidative stress and apoptosis, and that TEMPOL might sensitize tumor cells to the pro-apoptotic effects of cytotoxic agents.
Monti
E
E
Department of Structural and Functional Biology, University of Insubria, Varese, Italy. elena.monti@unimi.it
Supino
R
R
Colleoni
M
M
Costa
B
B
Ravizza
R
R
Gariboldi
M B
MB
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D012402:Rotenone / Q000494:pharmacology; D019810:Sodium Azide / Q000494:pharmacology; D013113:Spin Labels; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D000975:Antioxidants; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D013113:Spin Labels; D012402:Rotenone; D019810:Sodium Azide; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D014450:Electron Transport Complex III; D005978:Glutathione; C001803:tempol