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Inhibitory effect of dideoxyforskolin on cell death induced by ricin, modeccin, diphtheria toxin, and Pseudomonas toxin in MDCK cells.

We have found that 1,9-Dideoxyforskolin (DDF) strongly inhibited the cell death induced by ricin, modeccin, Pseudomonas toxin, and diphtheria toxin in MDCK cells, suggesting that these protein toxins have a DDF-sensitive common pathway leading to cell death. However, no significant effect of forskolin on these toxins was observed, implying that cAMP-independent DDF specific mechanism is responsible for the inhibitory effect. The protective effect of DDF against ricin-induced cell death was significantly reversed by the increase in extracellular Ca2+ concentrations. The addition of brefeldin A (BFA) also reversed the protective effect of DDF, while BFA alone slightly increased the cytotoxicity of ricin. The protein synthesis inhibitory activity of modeccin was strongly inhibited by DDF, while only partial inhibition of the activities of ricin and diphtheria toxin was observed. However, the activity of Pseudomonas toxin was enhanced by DDF rather than inhibited. Thus, the process leading to cell death and protein synthesis inhibition by these toxins may be separately affected by DDF, and the protective effect of DDF against toxin-induced cell death is distinct from its effect on protein synthesis inhibition by toxins. Forskolin and DDF slightly increased rather than inhibited the binding and the internalization of ricin to MDCK cells. Despite the strong inhibitory effect of DDF on toxin-induced cell death, DDF did not block toxin-induced DNA fragmentation. These results suggest that DNA fragmentation and cell death may be triggered through separate pathways during apoptosis caused by these toxins, and that a DDF-sensitive specific step may be present in the pathway leading to cell death.