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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3242-3250.
Prepublished online as a Blood First Edition Paper on July 14, 2005; DOI 10.1182/blood-2005-02-0460.
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Submitted February 2, 2005
Accepted April 30, 2005
Intracellular labile iron pools as direct targets of iron chelators. A fluorescence study of chelator action in living cells
Hava Glickstein, Rinat Ben El, Maya Shvartsman, and Z I Cabantchik*
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
* Corresponding author; email: ioav{at}cc.huji.ac.il.
The primary targets of iron chelators used for treating transfusional iron overload are prevention of iron ingress into tissues and its intracellular scavenging. The present study was aimed at elucidating the capacity of clinically important iron chelators such as deferiprone, desferrioxamine and ICL670 to: a. gain direct access to intracellular iron pools of key cells of iron accumulation (macrophages, hepatocytes and cardiomyocyte cell lines); b. chelate the labile iron present in discrete cell compartments/organelles and c. prevent labile iron involvement in the generation of reactive oxidant species. Chelation of cytosolic and organellar cell iron was visualized dynamically and quantitatively in living cells by fluorescence microscopic imaging of fluorescent metallo-sensors (used as iron-quenched complexes of calceins) targeted to either cytosol, endosome-lysosomes or mitochondria. The rate and extent of fluorescence recovery provided an in situ measure of the accessibility of chelators to particular cell sites/organelles. Complementary, fluorogenic redox probes, associated with cell compartments enabled identification of chelator-sensitive, localized reactive oxidant production. Our studies indicate that chelation by desferrioxamine is slow and is enhanced in cells with relatively high endocytic activities, while ICL670 and DFP readily enter most cells and efficiently reach the major intracellular sites of iron accumulation.
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