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 (O2 and H2O2) generated outside the cells (B14 line, model for neoplastic phenotype) in ***. The nitroxides prevented the decrease in the number of *** caused by exogenous O2- and H2O2 at concentrations which were not themselves cytotoxic. In the present study, we have also shown that a very 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 morphological characteristics of apoptosis. This effect was comparable to those observed for other nitroxyls under similar experimental conditions. Since the increase in the ROS generation followed by apoptotic changes of nuclei is the consistent recent finding in various experimental models of apoptosis, one fundamental question was raised: why nitroxide antioxidants paradoxically act as apoptosis inducers in vivo? Taking together the results presented here and in our previous works, it seems reasonable to suggest that nitroxide-antioxidants improve the endogenous "antioxidants reserve" and action can induce a reductive stress as opposed to an oxidative stress, triggering 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 substituent structure at 4-position of the nitroxide ring or its oxidation state are determinant for the degree of the observed differences in the apoptotic potency of nitroxide derivates in vivo.