Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition.
Onset of the mitochondrial permeability transition (MPT) causes both necrotic and apoptotic cell death in cultured hepatocytes. Salicylate lowers the threshold for onset of the MPT. In this study, our aim was to determine whether nontoxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and tert-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2 microM), a specific inhibitor of the MPT. In hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), salicylate accelerated cell killing after low-dose TNF-alpha (1 ng/ml), which by itself induced little apoptosis. Salicylate enhancement of apoptosis was associated with onset of the MPT and accelerated caspase 3 activation. Salicylate also augmented killing of MCF-7 human breast tumor cells by etoposide and PLC/PRF/5 human hepatoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, salicylate potentiates both necrotic and apoptotic cell killing by promoting onset of the MPT. Enhancement by salicylate of MPT-dependent apoptosis may play a role in protection by aspirin and other nonsteroidal anti-inflammatory drugs against colon, lung, and breast cancer.
Oh
Ki-Wan
KW
Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, 27599, USA.
Qian
Ting
T
Brenner
David A
DA
Lemasters
John J
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology; D010539:Permeability / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D007166:Immunosuppressive Agents; D007476:Ionophores; D012459:Salicylates; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin; D016572:Cyclosporine; D020122:tert-Butylhydroperoxide; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium