Free Radical Biology and Medicine

doi:10.1016/j.freeradbiomed.2005.11.003
Copyright =A9 2005 Elsevier Inc. All rights reserved.
Original Contribution
Iron chelation in the biological activity of curcumin

Yan Jiaoa, John Wilkinson IVa, c, E. Christine Pietschb, Joan L. Bussa,
Wei Wanga, c, Roy Planalpd, Frank M. Tortia, c and Suzy V. Tortib, c, ,


aDepartment of Cancer Biology, Wake Forest university Health Sciences,
Winston-Salem, NC 27157, USA
bBiochemistry, Wake Forest university Health Sciences, Winston-Salem,
NC 27157, USA
cComprehensive Cancer Center, Wake Forest university Health Sciences,
Winston-Salem, NC 27157, USA
dDepartment of Chemistry, university of New Hampshire, Durham NH, USA

Received 15 June 2005;  revised 29 October 2005;  accepted 1 November
2005.  Available online 29 November 2005.




Abstract
Curcumin is among the more successful chemopreventive compounds
investigated in recent years, and is currently in human trials to
prevent cancer. The mechanism of action of curcumin is complex and
likely multifactorial. We have made the unexpected observation that
curcumin strikingly modulates proteins of iron metabolism in cells and
in tissues, suggesting that curcumin has properties of an iron
chelator. Curcumin increased mRNA levels of ferritin and GSTa in
cultured liver cells. Unexpectedly, however, although levels of GSTa
protein increased in parallel with mRNA levels in response to curcumin,
levels of ferritin protein declined. Since iron chelators repress
ferritin translation, we considered that curcumin may act as an iron
chelator. To test this hypothesis, we measured the effect of curcumin
on transferrin receptor 1, a protein stabilized under conditions of
iron limitation, as well as the ability of curcumin to activate iron
regulatory proteins (IRPs). Both transferrin receptor 1 and activated
IRP, indicators of iron depletion, increased in response to curcumin.
Consistent with the hypothesis that curcumin acts as an iron chelator,
mice that were fed diets supplemented with curcumin exhibited a decline
in levels of ferritin protein in the liver. These results suggest that
iron chelation may be an additional mode of action of curcumin.

Keywords: Chelator; Chemoprevention; Curcumin; Iron; Ferritin;
Glutathione S-transferase; Free radicals

Abbreviations: GST, glutathione S-transferase; NQO1, NAD(P)H:quinone
oxidoreductase 1; IRPs, iron regulatory proteins; IRE, iron-responsive
element; SDS, sodium dodecyl sulfate; DMEM, Dulbecco's modified Eagle's
medium; TfR, transferrin receptor; BSA-PBS, bovine serum
albumin-phosphate-buffered saline; PMSF, phenylmethylsulfonyl fluoride


Supported in part by grants from the American Institute for Cancer
Research (S.V.T.), NIH Grant R37 DK 42412 (F.M.T.), and KO1 DK065876
(J.W.).
Corresponding author. Department of Biochemistry, Wake Forest
University Health Sciences, Winston Salem, NC 27157. Fax: +1 336 716
0255.

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