The paradoxical apoptotic effects of novel nitroxide antioxidants on yoshida sarcoma cells in vivo: A commentary

Here we show for the first time that the model nitroxide derivatives, free radical or its reduced piperidinium salt, suppressed cytotoxicity of ROS (O -2(.-) and H2O2) generated outside the cells (B14 line, model for neoplasti c phenotype) in vitro. The nitroxides prevented the decrease in the number of cells caused by exogenous O-2(.-) and H2O2 at concentrations which were not themselves cytotoxic. In the present study, we have also shown that a v ery substantial difference in the cell response occurred when the model rat tumor cells (Yoshida Sarcoma ascites) were treated in vivo with six novel synthesized nitroxide antioxidants. A number of tumor cells displayed morph ological characteristics of apoptosis. This effect was comparable to those observed for other nitroxyls under similar experimental conditions. Since t he increase in the ROS generation followed by apoptotic changes of nuclei i s the consistent recent finding in various experimental models of apoptosis , one fundamental question was raised: why nitroxide antioxidants paradoxic ally act as apoptosis inducers in vivo? Taking together the results present ed here and in our previous works, it seems reasonable to suggest that nitr oxide-antioxidants improve the endogenous "antioxidants reserve" and action can induce a reductive stress as opposed to an oxidative stress, triggerin g a cascade of dose-dependent processes involving indirectly an antioxidant mechanism(s) and resulting in the apoptotic death of cancer cells in vivo. The SAR (structure activity relationship) revealed that either the substit uent structure at 4-position of the nitroxide ring or its oxidation state a re determinant for the degree of the observed differences in the apoptotic potency of nitroxide derivates in vivo.