The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action

Goldie Y. L. Lui, Peyman Obeidy, Samuel J. Ford, Chris Tselepis, Danae M. Sharp, Patric J. Jansson, Danuta S. Kalinowski, Zaklina Kovacevic, David B. Lovejoy, Des R. Richardson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)

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 Fe-59 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.

Original languageEnglish
Pages (from-to)179-190
Number of pages12
JournalMolecular Pharmacology
Volume83
Issue number1
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

Keywords

  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • EFFECTIVE ANTIPROLIFERATIVE AGENTS
  • ATOMIC PHYSICOCHEMICAL PARAMETERS
  • METASTASIS SUPPRESSOR GENE
  • MYELOID-LEUKEMIA CELLS
  • CYCLIN D1 EXPRESSION
  • PANCREATIC-CANCER
  • QUANTITATIVE STRUCTURE
  • ANTITUMOR-ACTIVITY
  • REGULATED GENE-1

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