Potential Mechanisms for the Inhibition of Tumor Cell Growth by Manganese Superoxide Dismutase

Studies from many laboratories have shown that overexpression of manganese superoxide dismutase (MnSOD) inhibits the growth of numerous tumor cell types. The inhibition of tumor cell growth can be attributed to the increase in the steady-state levels of H₂O₂ as a result of the increased dismuting activity of MnSOD. Here we demonstrate that overexpression of MnSOD enhances the activity of the superoxide (O₂ ^•-)-sensitive enzyme aconitase, decreases the intracellular GSH/GSSG ratio, and dose-dependently inhibits pyruvate carboxylase activity. Thus, alterations in the steady-state concentrations of mitochondrial O₂ ^•- and H₂O₂ as a result of MnSOD overexpression can alter the metabolic capacity of the cell leading to inhibition of cell growth. Furthermore, we propose that MnSOD overexpression can modulate the activity of nitric oxide (^•NO) by preventing its reaction with O₂ ^•-. This hypothesis suggests that the redox environment of the mitochondria can be altered to favor the activity of ^•NO rather than peroxynitrite (ONOO^-) and may explain the enhanced toxicity of ^•NO-generating compounds toward MnSOD-overexpressing cell lines. These findings indicate that therapeutic strategies targeted at overexpressing MnSOD in tumor tissue may be more effective when used in combination with agents that deplete the oxidant-buffering and enhance the ^•NO-generating capacity of the tumor and host, respectively.