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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg045
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received September 9, 2002; accepted January 1, 2003
© 2003 Society of Toxicology

Carcinogenicity

Salicylate Enhances Necrosis and Apoptosis Mediated by the Mitochondrial Permeability Transition

Ki-Wan Oh 1, Ting Qian 1, David A. Brenner 2, John J. Lemasters 1*

1 Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7090, USA
2 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7090, USA

* To whom correspondence should be addressed. E-mail: lemaster{at}med.unc.edu.


  Abstract

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 non-toxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and t-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2µM), 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 non-steroidal anti-inflammatory drugs against colon, lung and breast cancer.


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