Superoxide dismutase: an emerging target for cancer therapeutics

Abstract

Superoxide dismutase (SOD) is a critical enzyme responsible for the elimination of superoxide radicals and is considered to be a key anti-oxidant in aerobic cells. Cellular consumption of oxygen is essential for oxidative phosphorylation during ATP generation in the mitochondria, yet this cellular metabolism also leads to the production of reactive oxygen species (ROS), including the superoxide radical (O(2)(*)(-)) and hydrogen peroxide (H(2)O(2)). Accumulation of ROS results in cellular oxidative stress and, if not corrected, can lead to the damage of important biomolecules such as membrane lipids, proteins and DNA. Prolonged accumulation of high levels of free radicals in cells may cause irreversible cellular injury and ultimately result in cell death. Since SOD is the key enzyme in the first metabolic step of superoxide elimination, deficiency in SOD or inhibition of the enzyme activity may cause severe accumulation of O(2)(*)(-) in cells and lead to cell death. Thus, inhibition of SOD may provide a novel way to kill cancer cells. Due to dysfunction in the regulation of cell growth, cancer cells are active in energy metabolism, and thus produce high levels of O(2)(*)(-) and other ROS and are under constant oxidative stress. This may render the malignant cells more dependent on SOD to eliminate the toxic superoxide radicals and thus potentially more sensitive to SOD inhibitors. It is a plausible hypothesis that inhibition of SOD may preferentially kill malignant cells through a free radical-mediated mechanism. This article will review evidence that suggests SOD as an emerging therapeutic target for cancer treatment. The relevant clinical implications and potential risk will also be discussed.