Abstract
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
Highlights
Acute lymphocytic leukemia (ALL) is a rare hematological malignancy, contributing to about 20% of new acute leukemias [1]
According to the reports of Benadiba et al [15], DFO has significantly affected the survival of T lymphoblastic leukemia/lymphoma cells to induce apoptosis and demonstrated synergistic action with three ALL-specific drugs: L-asparaginase, doxorubicin, and dexamethasone
To examine the abundance of cellular labile iron pool in the ALL cell lines Jurkat and NALM-6 cells, the calcein-AM assay suggested that Dex effectively increased the concentration of intracellular iron, whereas DFO effectively decreased the concentration of intracellular iron in Figures 1(c) and 1(d)
Summary
Acute lymphocytic leukemia (ALL) is a rare hematological malignancy, contributing to about 20% of new acute leukemias [1]. Erefore, there is an urgent need for new treatment methods to improve the survival rate of ALL patients who have failed treatment or relapsed after the initial response. Iron deficiency reduced the aggressiveness of a variety of tumor cells, which has important clinical value in the treatment of leukemia [8, 9]. Iron chelator triapine has been reported to be able to inhibit the ribonucleotide reductase activity and tumor growth both in vivo and in vitro and has been involved in the phase I and phase II clinical trials [10]. According to the reports of Benadiba et al [15], DFO has significantly affected the survival of T lymphoblastic leukemia/lymphoma cells to induce apoptosis and demonstrated synergistic action with three ALL-specific drugs: L-asparaginase, doxorubicin, and dexamethasone
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