Tumour cell killing by tumour necrosis factor: inhibition by anaerobic conditions, free-radical scavengers and inhibitors of arachidonate metabolism.
Previous work on the mechanism of tumour-cell killing by the macrophage product tumour necrosis factor (TNF) is consistent with a free radical-induced process. In this study, free-radical involvement was sought by (i) investigating the effects on TNF cytolysis of anaerobic conditions, free-radical scavengers and inhibitors of two potential pathways of free-radical generation (oxidative phosphorylation and arachidonate metabolism) and (ii) looking for increased malonyldialdehyde (MDA) production in TNF-treated cells (MDA is a free radical-induced lipid peroxidation product). Although TNF cytolysis of L929 cells was inhibited by anaerobic conditions, only limited effects were seen with free-radical scavengers. Suppression of arachidonate metabolism by steroids effectively inhibited TNF cytolysis but the mitochondrial poison rotenone did not. There was a marked, but late, increase in MDA production in TNF-treated cells. Overall, these results indicate that if free radicals are involved it is at a late stage in the cytolytic process. However the most striking observation in this study is that arachidonate metabolism is an essential link in the cytolytic process.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D005609:Free Radicals; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D001095:Arachidonic Acids; D005609:Free Radicals; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen