RT Journal Article
SR Electronic
T1 The Iron Chelator, Deferasirox, as a Novel Strategy for Cancer Treatment: Oral Activity Against Human Lung Tumor Xenografts and Molecular Mechanism of Action
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.081893
DO 10.1124/mol.112.081893
A1 Goldie Y. L. Lui
A1 Peyman Obeidy
A1 Samuel J. Ford
A1 Chris Tselepis
A1 Danae M. Sharp
A1 Patric J. Jansson
A1 Danuta S. Kalinowski
A1 Zaklina Kovacevic
A1 David B. Lovejoy
A1 Des R. Richardson
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/10/16/mol.112.081893.abstract
AB Deferasirox is an orally-effective iron chelator currently used for the treatment of iron (Fe) overload disease and has been implemented as an alternative to the "gold standard" chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO has anti-cancer activity due to its ability to deplete cancer cells of Fe. 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 when compared to DFO. Further, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular 59Fe and inhibiting iron uptake from Tf 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 anti-tumor 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 (NDRG1), and up-regulated the cyclin-dependent kinase inhibitor p21CIP1/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 anti-tumor agent against solid tumors.