The egcSEs comprise five genetically linked
staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these
proteins was recently used to treat advanced
lung cancer with
pleural effusion. We investigated the hypothesis that egcSEs induce
nitrous oxide (NO) and associated
cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human
tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11-25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed
NO synthase and generated robust levels of
nitrite (range: 200-250 μM), a breakdown product of NO; this reaction was inhibited by
NG-monomethyl-L-arginine (
L-NMMA) (0.3 mM), an
NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent
tumor cell apoptosis in a broad panel of human
tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by
L-NMMA, anti-TNF-α
antibodies, respectively, and a combination thereof. A hierarchy of
tumor cell sensitivity to these CFSs was as follows: lung
carcinoma >
osteogenic sarcoma >
melanoma >
breast carcinoma >
neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent
tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce
NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human
tumor cells.