Reactive Oxygen Species Synergize to Potently and Selectively Induce Cancer Cell Death

A distinctive feature of cancer cells is their elevated levels of reactive oxygen species (ROS), a trait that can cause cancer cells to be more sensitive to ROS-inducing agents than normal cells. ROS takes several forms, each with different reactivity and downstream consequence. Here we show that simultaneous generation of superoxide and hydrogen peroxide within cancer cells results in significant synergy, causing potent and selective cancer cell death. In these experiments superoxide is generated using the NAD(P)H quinone oxidoreductase 1 (NQO1) substrate deoxynyboquinone (DNQ), and hydrogen peroxide is generated using the lactate dehydrogenase A (LDH-A) inhibitor NHI-Glc-2. This combination reduces tumor burden and prolongs survival in a mouse model of lung cancer. These data suggest that simultaneous induction of superoxide and hydrogen peroxide can be a powerful and selective anticancer strategy.