Protection of cells from menadione-induced apoptosis by inhibition of lipid peroxidation.
Menadione is a commonly used compound that causes oxidative stress. We investigated the influence of lipid peroxidation on the apoptotic response of mouse myogenic C2C12 cells following menadione-induced oxidative stress. The presence of hypodiploid cells and phosphatidylserine translocation were assayed to detect apoptotic cells. Menadione at 10-40 micro M induced cell apoptosis. Menadione at dose of 80 micro M induced both apoptosis and necrosis. At a 160 micro M dosage, menadione induced cell necrosis. Caspase 3 activation is required for menadione-induced apoptosis. Incubation of cells with 40 micro M menadione resulted in the depletion of cellular glutathione and increased lipid peroxidation. Pre-treatment of cells with cysteine suppressed the menadione-induced apoptosis and prevented changes in reactive oxygen species levels, glutathione levels and lipid peroxidation. Pre-treatment of cells with deferoxamine mesylate, an iron chelator, also reduced both menadione-induced apoptosis and lipid peroxidation. However, this did not prevent menadione-induced glutathione depletion. Thus, the inhibition of lipid peroxidation by deferoxamine mesylate prevented apoptosis even though cellular glutathione remained depleted. Our data suggest that menadione-induced apoptosis is directly linked to iron-dependent lipid peroxidation.
Chiou
Tzeon-Jye
TJ
Section of Medical Oncology, Department of Medicine, Veterans General Hospital, Taipei, Taiwan ROC. bio1005@mails.fju.edu.tw
Chu
Sin-Tak
ST
Tzeng
Woan-Fang
WF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004347:Drug Interactions; D005434:Flow Cytometry; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology*; D011003:Ploidies; D017382:Reactive Oxygen Species / Q000378:metabolism; D024483:Vitamin K 3 / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D007502:Iron Chelating Agents; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D024483:Vitamin K 3; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D003676:Deferoxamine; D003545:Cysteine