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.