Targeted Inhibition of Superoxide Dismutase 1 Is Effective in NSCLC

Accumulation of increased reactive oxygen species (ROS) in cancer cells promotes the upregulation of antioxidant proteins as an adaptive response to prevent ROS-mediated cell death. Recent studies have suggested that the antioxidant enzyme superoxide dismutase 1 (SOD1), which is overexpressed in human lung tumors and protects against oxidative stress by converting superoxide to hydrogen peroxide (H₂O₂), is a potential therapeutic target in non–small cell lung cancer (NSCLC) cells. However, the molecular mechanisms by which SOD1 blockade induces cancer cell death and whether this therapeutic strategy is effective in preclinical mouse models of NSCLC remain unknown. Glasauer and colleagues found that the small molecule SOD1 inhibitor ATN-224 selectively stimulated apoptosis and impaired transformation in human NSCLC cell lines but not nontransformed normal bronchial epithelial cells, which exhibit lower basal ROS levels. Surprisingly, ATN-224 treatment enhanced both intracellular superoxide and H₂O₂ levels via superoxide-mediated inactivation of the H₂O₂ scavenger enzyme glutathione peroxidase (GPX) and subsequent H₂O₂-induced hyperoxidation of the scavenger peroxiredoxin. This increase in H₂O₂ resulted in activation of p38 MAPK (also known as MAPK14) signaling and downregulation of the antiapoptotic protein myeloid cell leukemia sequence 1 (MCL1), and was required to stimulate BIM- and PUMA-dependent programmed cell death in both human and murine lung cancer cells. Furthermore, single-agent ATN-224 treatment triggered apoptosis and diminished lung tumor burden in the Kras^G12D;Trp53-null preclinical mouse model of NSCLC and synergized with ABT-263 (navitoclax), an inhibitor of the antiapoptotic proteins BCL2 and BCLXL, and buthionine sulphoximine, a glutathione scavenger that inhibits GPX, to augment NSCLC cell death in vitro. These results suggest that SOD1 inhibition with ATN-224 may be therapeutically beneficial for patients with KRAS-driven NSCLC and support further development of pro-oxidant drug combinations that limit cancer cell adaptation to oxidative stress.

Glasauer A, Sena LA, Diebold LP, Mazar AP, Chandel NS. Targeting SOD1 reduces experimental non–small-cell lung cancer. J Clin Invest 2013 Dec 2 [Epub ahead of print].