GANGLIOSIDES PROTECT FROM TNF-ALPHA-INDUCED APOPTOSIS

The modulation of tumor necrosis factor alpha-mediated cytotoxicity by gangliosides was analyzed. When cells of the TNFalpha-sensitive fibrosarcoma cell line L929 were incubated for 16 h with recombinant TNFalpha (156 or 312 pg/ml), they were lysed to 65.2% or 78.0%, respectively. The presence of a bovine brain ganglioside mixture (BBG, Cronassial) inhibited the TNFalpha-mediated lysis in a dose-dependent manner (IC50 almost-equal-to 1 mg/ml). Maximum inhibition was achieved with 2 mg/ml BBG (82.6% inhibition for 156 pg/ml TNFalpha and 88.5% inhibition for 312 pg/ml TNFalpha). In situ nick translation revealed that BBG (2 mg/ml) significantly reduces the number of cells with TNFalpha-induced DNA-strand breaks from 71.2% to 6.6% (P<0.0001), indicating a protection against TNFalpha-mediated apoptosis. We conclude that BBG prevents the cytotoxic action of TNFalpha on tumor cells. The inhibitory effect may be due to an interference of gangliosides with intracellular signal transduction pathways, resulting in an inhibition of the activation of DNA-cleaving endonucleases.