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Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis

2002; Elsevier BV; Volume: 139; Issue: 1 Linguagem: Inglês

10.1016/s0009-2797(01)00295-2

1872-7786

Julie C. Kern, James P. Kehrer,

Pesticide Exposure and Toxicity

Due to the dominating roles that caspases play in the apoptotic cascade, their activities appear to be a primary factor in the death pathway (apoptosis versus oncosis/necrosis) decision. In murine FL5.12 proB lymphocytes, the cellular consequences of acrolein treatment included a lack of typical apoptotic features in preference to oncosis/necrosis. Oncosis/necrosis was apparent by detection of a reduction in intracellular ATP concentration, increased plasma membrane leakage (measured by LDH release and flow cytometric detection of propidium iodide uptake) and morphological criteria. Analysis of acrolein-treated cell lysates or recombinant caspase enzymes showed overall dose-dependent decreases in caspase-3, -8 and -9 activities. In addition to acrolein's effect on intracellular caspases, it was also able to alter caspase-dependent apoptosis induced by secondary treatment with etoposide or following cytokine withdrawal. Acrolein at doses ≥20 μM circumvented etoposide or interleukin-3 withdrawal induced apoptosis. When acrolein was combined with mechlorethamine, another alkylating agent not dependent on caspases for its cell death signaling, necrosis was increased in a dose-dependent manner. Overall, these data suggest that caspase inhibition plays an important role in the cell death pathway decision, particularly with treatments dependent on the caspase cascade to induce apoptosis.