Iron, an indispensable element for life, is involved in all kinds of important physiological activities. Iron promotes cell growth and proliferation, but it also causes oxidative stress damage. The body has a strict regulation mechanism of iron metabolism due to its potential toxicity. As a cancer of the bone marrow and blood cells, leukemia threatens human health seriously. Current studies suggest that dysregulation of iron metabolism and subsequent accumulation of excess iron are closely associated with the occurrence and progress of leukemia. Specifically, excess iron promotes the development of leukemia due to the pro-oxidative nature of iron and its damaging effects on DNA. On the other hand, leukemia cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide new insights for approaches to the treatment of leukemia. This review summarizes physiologic iron metabolism, alternations of iron metabolism in leukemia and therapeutic opportunities of targeting the altered iron metabolism in leukemia, with a focus on acute leukemia.

Iron is an essential element for the growth and proliferation of cells. Cellular iron uptake, storage, utilization and export are tightly regulated to maintain iron homeostasis. However, cellular iron metabolism pathways are disturbed in most cancer cells. To maintain rapid growth and proliferation, cancer cells acquire large amounts of iron by altering expression of iron metabolism- related proteins. In this paper, normal cellular iron metabolism and the alterations of iron metabolic pathways in cancer cells were summarized. Therapeutic strategies based on targeting the altered iron metabolism were also discussed and disrupting redox homeostasis by intracellular high levels of iron provides new insight for cancer therapy. Altered iron metabolism constitutes a promising therapeutic target for cancer therapy.

Osteosarcoma is a common malignant bone tumor in clinical orthopedics. Iron chelators have inhibitory effects on many cancers, but their effects and mechanisms in osteosarcoma are still uncertain. Our in vitro results show that deferoxamine (DFO) and deferasirox (DFX), two iron chelators, significantly inhibited the proliferation of osteosarcoma cells (MG-63, MNNG/HOS and K7M2). The viability of osteosarcoma cells was decreased by DFO and DFX in a concentration-dependent manner. DFO and DFX generated reactive oxygen species (ROS), altered iron metabolism and triggered apoptosis in osteosarcoma cells. Iron chelator-induced apoptosis was due to the activation of the MAPK signaling pathway, with increased phosphorylation levels of JNK, p38 and ERK, and ROS generation; in this process, the expression of C-caspase-3 and C-PARP increased. In an orthotopic osteosarcoma transplantation model, iron chelators (20 mg/kg every day, Ip, for 14 days) significantly inhibited the growth of the tumor. Immunohistochemical analysis showed that iron metabolism was altered, apoptosis was promoted, and malignant proliferation was reduced with iron chelators in the tumor tissues. In conclusion, we observed that iron chelators induced apoptosis in osteosarcoma by activating the ROS-related MAPK signaling pathway. Because iron is crucial for cell proliferation, iron chelators may provide a novel therapeutic strategy for osteosarcoma.