The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action

Abstract

Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular 59 Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21 CIP1/WAF1 while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

“…We observed a dose-dependent antiproliferative activity of DFX in pancreatic cancer cell lines, consistent with the results of previous studies in esophageal cancer cell lines [22] or lung cancer cell lines [23]. Although a number of studies have attempted to elucidate the anti-cancer mechanisms of iron chelators, their mechanisms are not well known [12].…”

“…As DFX is given to patients orally, we administered DFX as a saline suspension given orally in accordance with previous studies [22, 23]. DFX administered orally at 160 and 200 mg/kg (every second day, three treatments per week for 21 days) resulted in marked inhibition of tumor growth as determined by measurements of tumor volume and tumor weight (Fig.…”

“…On the other hand, DFX, a recently identified iron chelator, can be administered orally once daily because it is orally active and has a long half-life of 7–18 h. DFX is currently used for the treatment of iron-overload disease and is considered an alternative to DFO [16]. The antiproliferative activity of DFX has been investigated in various cancers [22, 23, 29, 30]. However, there have previously been no studies of the effects of DFX in pancreatic cancer; this study is the first to elucidate the antiproliferative activity of DFX against pancreatic cancer cells.…”

Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease

“…Deferasirox (Dfx), a tridentate chelator that allows iron redox cycling, is an orally available iron chelator that has promise as an antineoplastic. Dfx has been shown to inhibit the growth of various types of malignant cells in cell culture [66,67] and in xenograft models [68,69]. There is also a case report of Dfx contributing to complete remission in a patient with recurrent acute myelogenous leukemia [70].…”

Anticoagulation, ferrotoxicity and the future of translational lung cancer research

“…Aberrant tumor cell iron handling is central to its toxicity (43,44). Studies underway should clarify effects of iron in experimental (45)(46)(47) and human (48)(49)(50) malignancy. Little information is available on effects of iron reduction on blood coagulation.…”