title: Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo.
abstract: OBJECTIVE
  Growing 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  Deferasirox 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
  The 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.
authors.affiliation: School of Cancer Sciences, Department of Medical & Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Ford
authors.forename: P
authors.initials: P
authors.lastname: Obeidy
authors.forename: D B
authors.initials: DB
authors.lastname: Lovejoy
authors.forename: M
authors.initials: M
authors.lastname: Bedford
authors.forename: L
authors.initials: L
authors.lastname: Nichols
authors.forename: C
authors.initials: C
authors.lastname: Chadwick
authors.forename: O
authors.initials: O
authors.lastname: Tucker
authors.forename: G Y L
authors.initials: GY
authors.lastname: Lui
authors.forename: D S
authors.initials: DS
authors.lastname: Kalinowski
authors.forename: P J
authors.initials: PJ
authors.lastname: Jansson
authors.forename: T H
authors.initials: TH
authors.lastname: Iqbal
authors.forename: D
authors.initials: D
authors.lastname: Alderson
authors.forename: D R
authors.initials: DR
authors.lastname: Richardson
authors.forename: C
authors.initials: C
authors.lastname: Tselepis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077588:Deferasirox; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D003676:Deferoxamine; D002945:Cisplatin; D000077588:Deferasirox