title: Subcellular distribution of desferrioxamine and hydroxypyridin-4-one chelators in K562 cells affects chelation of intracellular iron pools.
abstract: The interactions of iron chelators with intracellular iron pools have been examined by measuring the subcellular distribution of radiolabelled desferrioxamine (DFO) and the orally active hydroxypyridinone (HPO) chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94), as well as the ability of these chelators to modify the subcellular distribution of 59Fe delivered by the receptor mediated endocytosis of transferrin. K562 cells were pulsed with 59Fe transferrin and challenged with DFO or CP94 (100 microM IBE) for 20 or 240 min and then subjected to subcellular fractionation. At 20 min there was a significant decrease (P < 0.05) in both lysosomal/particulate 59Fe (75% of control) and cytosolic 59Fe ferritin (50% of control) in cells incubated with CP94, unlike cells treated with DFO where no decrease was observed. By 240 min, in addition to the above, 59Fe accumulation was significantly decreased in the nuclear, mitochondrial, and low molecular weight cytosolic fractions with CP94 (P < 0.05). With DFO a significant decrease in 59Fe in only the lysosomal/particulate and cytosolic ferritin compartments was observed at 240 min (P < 0.05). At this time, however, there was a significant accumulation of both cytosolic low molecular weight 59Fe and cytosolic DFO. The relatively rapid decrease of 59Fe within intracellular compartments seen with CP94 compared to DFO was paralleled by a significantly higher accumulation of CP94 than DFO in nuclear, lysosomal/particulate and low molecular weight cytosolic compartments at 20 min (P < 0.05). These results suggest that transferrin derived endosomal iron may be chelated by HPOs, unlike DFO, due to their faster uptake into these organelles. The more rapid access of HPOs than DFO to certain intracellular iron pools may explain the greater possibility of HPOs to inhibit proliferation of cells in vivo.
authors.affiliation: Department of Clinical Haematology, University College Medical School, London.
authors.forename: K P
authors.initials: KP
authors.lastname: Hoyes
authors.forename: J B
authors.initials: JB
authors.lastname: Porter
mesh_terms: D003600:Cytosol / Q000378:metabolism; D003676:Deferoxamine / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000378:metabolism; D008970:Molecular Weight; D011728:Pyridones / Q000493:pharmacokinetics* / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D007502:Iron Chelating Agents; D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D007501:Iron; D003676:Deferoxamine