Mitochondrially-targeted deferoxamine induces mitophagy and acts as anti-cancer agent in vivo

Abstract

Iron is a crucial nutrient for proliferating cancer cells. Thus, we have synthesized a mitochondrially targeted derivative of the iron chelator deferoxamine (mDFO) and evaluated its ability to selectively eliminate cancer cells both in vitro and in vivo. Viability of human cancer cells treated with mDFO was assessed by crystal violet or annexin V staining. ROS production was assessed through fluorescent probes MitoSOX and DCF. Blue native electrophoresis and Seahorse were used to analyse mitochondrial function. The in vivo effect of mDFO was assessed by xenografting triple negative breast cancer cells in NOD/Scid mice. Our results show that mDFO is at least 100-fold more efficient than DFO in killing cancer cells. In addition, mDFO was shown to reduce respiration and dramatically decrease the amount and composition of mitochondrial respiratory supercomplexes. Both the latter effects might trigger the observed increase in mitochondrial superoxide production, the fragmentation of mitochondria and the activation of mitophagy. Importantly, in vivo results show that mDFO is effective in slowing the tumour growth. mDFO represents an effective drug to inhibit tumour growth in vivo and might represent the lead compound in a new generation of anti-cancer agents based on mitochondrial iron chelation.