Iron depletion: possible cause of tumor cell cytotoxicity induced by activated macrophages

The experiments reported here provide a possible molecular mechanism for the activated macrophage cytotoxic effect. Tumor cells that develop cytostasis and inhibition of mitochondrial respiration in response to cocultivation with activated macrophages release a significant fraction of their intracellular iron-59 content. Kinetic studies show that specific release of iron-59 from target cells begins 4-6 hours after initiating cocultivation which is the time point that inhibition of DNA synthesis is first detected. Treatment of tumor cells with metabolic inhibitors causing inhibition of respiration, protein synthesis, RNA synthesis, and DNA synthesis to a similar or greater extent than that caused by activated macrophages does not induce release of intracellular iron-59. It is significant that mitochondrial respiration and DNA replication, both strongly inhibited in target cells by activated macrophages, are metabolic pathways with enzymatic activity vulnerable to inhibition by depletion of intracellular iron.