The Role of Ferric Nitrilotriacetate in Renal Carcinogenesis and Cell Death: From Animal Models to Clinical Implications

Simple Summary Iron is essential for cellular growth and survival. As a consequence, iron deficiency causes pleiotropic effects on the organism, while iron overload is also deleterious by means of oxidative tissue injury, which causes hepatic cirrhosis, diabetes mellitus, and cardiomyopathy in humans. Non-heme iron comprises ferric ion (Fe(III)), which is much more prominent in the transferrin, ferritin, or labile iron pool than the ferrous ion (Fe(II)); in contrast, ferrous ion yields more reactive oxygen species (ROS) than ferric ion does. In rodents, ferric nitrilotriacetate (Fe-NTA) elicits hepatic and renal oxidized lipids via a glutathione-cycle-dependent iron reduction that eventually causes renal cell carcinoma (RCC). In addition to iron-mediated carcinogenesis, ferroptosis is triggered by the iron-dependent accumulation of lipid peroxidation to lethal levels. Here, the mechanisms of iron- and ROS-mediated RCC and the therapeutic possibility of ferroptosis are discussed. Iron is essential for cellular growth, and various ferroproteins and heme-containing proteins are involved in a myriad of cellular functions, such as DNA synthesis, oxygen transport, and catalytic reactions. As a consequence, iron deficiency causes pleiotropic effects, such as hypochromic microcytic anemia and growth disturbance, while iron overload is also deleterious by oxidative injury. To prevent the generation of iron-mediated reactive oxygen species (ROS), ferritin is synthesized to store excess iron in cells that are consistent with the clinical utility of the serum ferritin concentration to monitor the therapeutic effect of iron-chelation. Among the animal models exploring iron-induced oxidative stress, ferric nitrilotriacetate (Fe-NTA) was shown to initiate hepatic and renal lipid peroxidation and the development of renal cell carcinoma (RCC) after repeated intraperitoneal injections of Fe-NTA. Here, current understanding of Fe-NTA-induced oxidative stress mediated by glutathione-cycle-dependent iron reduction and the molecular mechanisms of renal carcinogenesis are summarized in combination with a summary of the relationship between the pathogenesis of human RCC and iron metabolism. In addition to iron-mediated carcinogenesis, the ferroptosis that is triggered by the iron-dependent accumulation of lipid peroxidation and is implicated in the carcinogenesis is discussed.