Mechanism of redox injury

The main goal of this project is to gain an understanding of the role of oxidative stress in normal tissue injury induced by prototype anticancer drugs, Doxorubicin (Dox) and Paclitaxel (Ptx), two structurally different, widely used chemotherapy drugs that generate reactive oxygen species (ROS). We will investigate the mechanisms by which ROS generation contributes to the injury of cardiac and neuronal tissues. We propose that ROS-generating anticancer drugs can cause cardiac and central nervous system (CNS) injury by direct and indirect mechanisms. For direct mechanisms, ROS-generating drugs can accumulate in the tissue and cause direct oxidative injury. This direct injury can be modified by the effects mediated by indirect mechanisms. A major contributor of the indirect mechanism is a TNF-á-mediated process. This process is initiated by the direct intravascular oxidative modification of plasma proteins by ROS followed by release of TNF-á that can initiate a cascade of events that result in the inactivation of manganese superoxide dismutase (MnSOD), a major antioxidant defense enzyme in neuronal mitochondria. Thus, the intracellular effects of both the direct and indirect mechanisms converge at the mitochondria and require the ability of the multidrug resistance protein 1 (MRP1) to remove oxidatively modified products, a process essential for the protection against ROS-generating chemotherapeutics.