Antioxidant treatment versus pro-oxidant treatment as a therapy for hematologic malignancy. ROS production in myeloid leukemia cells may present an exploitable therapeutic target. Both antioxidant and pro-oxidant strategies may be effective, but both have potential advantages and disadvantages. The effects of antioxidant treatment on malignant cells (left side of figure) are likely to include reduced proliferative drive, which may reduce tumor burden and also protect nonmalignant cells from oxidative damage, particularly when administered in combination with chemotherapeutic (CT) agents. However, there are also concerns that suppression of cell cycle and antagonism of chemotherapy-induced ROS may adversely affect treatment efficacy. Pro-oxidant treatment (right side of figure) induces further ROS beyond that already produced by the malignant cell, either by depleting antioxidant defenses or augmenting ROS production. Treatment-induced oxidative stress combined with the intrinsic stress already present in the malignant cell leads to lipid peroxidation, oxidation of redox-sensitive residues within proteins, and DNA oxidation resulting in base-transversion and DSBs. Furthermore, damage to the electron transport chain and mutations in mitochondrial DNA can lead to a cycle of increased mitochondrial ROS. Elevated ROS has also been shown to contribute to cell-cycle progression in some contexts, which may increase tumor burden, but may simultaneously sensitize malignant cells to mainstay treatments. Although these factors may lead to induction of apoptosis in malignant cells, elevated ROS will increase the DNA mutation rate in any cells that fail to undergo apoptosis, possibly leading to selection of resistant clones. Furthermore, ROS generated by malignant cells may have paracrine effects on ROS signaling and oxidative damage in nonmalignant cells, and this effect would be augmented during treatment with pro-oxidants.