Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo

Abstract

BACKGROUND AND PURPOSEGrowing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti-tumour activity, although whether iron chelators show activity against oesophageal cancer is not known. EXPERIMENTAL APPROACHThe effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed. KEY RESULTSDeferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels. CONCLUSIONS AND IMPLICATIONSThe clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.

Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma

“…A previous report also confirmed the efficacy of DFX using the same dose in an esophageal cancer xenograft mice model[31]. However, there were no responders for DFX therapy in our clinical study; one patient exhibited SD, and four patients exhibited PD.…”

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].…”

Iron Deprivation in Cancer––Potential Therapeutic Implications

“…DFX is an appealing agent as it is a very effective iron chelator and can be orally administered. It has been tested in vitro against lung carcinoma, neuroepithelioma, and esophageal carcinoma, and has been found to inhibit proliferation in all of these tumor types [113,114]. DFX has also been used in xenograft mouse models of lung cancer, and been found to inhibit tumor growth with essentially no toxic effect to the normal tissue [113].…”