The rate of absorption and excretion of iron in the body is maintained at a steady state. However, in the case of aplastic anemia, myelodysplastic syndrome, or other kinds of anemia, the regular cycle of blood transfusion causes iron to accumulate faster than it can be excreted. With no particular means to excrete this excess iron, it can induce damage to the organs of the body [21
]. Various iron chelators have been used as therapeutic agents to remove the stored iron in the body, thereby preventing organ damage. However, the antiproliferative effects of iron chelating agents have only recently been recognized [22
]. Deferoxamine, which is an iron chelator, has increased the survival rate of patients with iron overload [25
], and some studies have also shown its anticancer effects [8
]; however, this drug must be administered by injection rather than orally, and only 10% of patients are being treated with deferoxamine [28
The oral iron chelator deferasirox has been recently developed and is, currently, in clinical trials, with its anticancer effects being reported [19
]. However, the mechanism of the drug's antiproliferative effects is yet to be determined. Chantrel-Groussard et al. reported that deferasirox can inhibit polyamine synthesis and block cell cycle in the G2-M phase by decreasing ornithine decarboxylase and spermidine N1-acethyltransferase activities as well as ornithine decarboxylase mRNA levels. They concluded that the anticancer and antiproliferative effects of deferasirox in hepatocellular carcinoma are distinct from its iron chelating activity [29
There have also been reports of deferasirox acting as a potent NF-κB inhibitor in patients with myelodysplastic syndrome [12
]. Recently, Ohyashiki et al. reported that deferasirox inhibited proliferation of acute myeloid leukemia cells due to an increase in REDD1 (Regulated in development and DNA damage response) and tuberous sclerosis complex 2 (TSC2). This inhibited the phosphorylation of mTOR and decreased the phosphorylation of p70S6 kinase and S6 ribosomal protein, thus leading to inhibited proliferation of leukemic cells [19
]. These findings lead us to consider that deferasirox also may have anticancer effects in malignant lymphoma cell lines.
In our study, we demonstrated that deferasirox has antiproliferative effects in human malignant lymphoma cell lines. The MTT assay showed that deferasirox induces cytotoxic effects in 3 malignant lymphoma cell lines after a 24-h treatment. Annexin/PI staining demonstrated that deferasirox induces early apoptosis in the same malignant cell lines. Western blot analysis showed an increase in the cleavage of caspase 3/7 and caspase 9 as well in the expression of P53 and Bax. To examine other cell signaling pathways, we evaluated targets in the PI3K/Akt/mTOR pathway, NF-κB signaling, and the RAS/JNK pathway, but we did not obtain significant results.
In conclusion, our study showed that deferasirox induces DNA damage in malignant lymphoma cell lines, thereby causing an increase in P53 expression and an induction in early apoptosis through Bcl2-Bax. However, the mechanism by which deferasirox causes DNA damage is not well understood. In addition, the induction of early apoptosis alone may not be sufficient to account for the anticancer effects of deferasirox. Therefore, further studies are required, perhaps, using siRNA against P53 or Bax; furthermore, in vivo animal experiments using nude mouse are needed to validate the results of the effects of deferasirox. Overall, our data suggest that deferasirox is a promising new antiproliferative agent for use in the treatment of malignant lymphoma.