Mitochondrial iron chelation as a novel anti-cancer strategy

Abstract

Iron is an indispensable micronutrient required for function of key cellular enzymes required for DNA replication and repair, and for mitochondrial respiration and metabolism. Within cells, iron is primarily utilized in mitochondria, where it is essential for the synthesis of Fe-S clusters and heme. The role of iron in carcinogenesis is widely accepted, and tumor cells require higher amounts of iron for their survival and proliferation. Indeed, iron chelation has been proposed as an alternative strategy to target cancer cells. Therefore, we synthesized a mitochondrially targeted derivative of the iron chelator deferoxamine (mDFO) and evaluated its ability to eliminate cancer cells selectively. Our results show that mDFO is at least 100-fold more efficient than DFO in killing breast cancer cells. Moreover, mDFO was able to reduce mitochondrial respiration and aconitase activity, increase mitochondrial and cellular ROS production, and trigger the activation of mitophagy. Taken together, our data strongly support the role of mDFO as a novel and efficient compound in the selective elimination of cancer cells.