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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 781-792
The Potential of Iron Chelators of the Pyridoxal Isonicotinoyl
Hydrazone Class as Effective Antiproliferative Agents III: The Effect
of the Ligands on Molecular Targets Involved in Proliferation
G. Darnell and
D.R. Richardson
From the Department of Medicine, University of Queensland, Royal
Brisbane Hospital, Brisbane, Queensland, Australia.
We have identified specific iron (Fe) chelators of the pyridoxal
isonicotinoyl hydrazone (PIH) class that are far more effective ligands
than desferrioxamine (DFO; Richardson et al, Blood 86:4295, 1995; Richardson and Milnes, Blood 89:3025, 1997). In the
present study, we have compared the effect of DFO and one of the most active chelators (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 311) on molecular targets involved in proliferation. This was performed
to further understand the mechanisms involved in the antitumor activity
of Fe chelators. Ligand 311 was far more active than DFO at increasing
Fe release from SK-N-MC neuroepithelioma and BE-2 neuroblastoma cells
and preventing Fe uptake from transferrin. Like DFO, 311 increased the
RNA-binding activity of the iron-regulatory proteins (IRPs). However,
despite the far greater Fe chelation efficacy of 311 compared with DFO,
a similar increase in IRP-RNA binding activity occurred after 2 to 4 hours of incubation with either chelator, and the binding activity was
not inhibited by cycloheximide. These results suggest that,
irrespective of the Fe chelation efficacy of a ligand, an increase
IRP-RNA binding activity occurred via a time-dependent step that did
not require protein synthesis. Further studies examined the effect of
311 and DFO on the expression of p53-transactivated genes that are crucial for cell cycle control and DNA repair, namely WAF1,
GADD45, and mdm-2. Incubation of 3 different cell lines
with DFO or 311 caused a pronounced concentration- and time-dependent
increase in the expression of WAF1 and GADD45 mRNA, but not mdm-2 mRNA. In accordance with the distinct differences in Fe chelation efficacy and antiproliferative activity of DFO and 311, much higher
concentrations of DFO (150 µmol/L) than 311 (2.5 to 5 µmol/L) were
required to markedly increase GADD45 and WAF1 mRNA levels. The increase
in GADD45 and WAF1 mRNA expression was seen only after 20 hours of incubation with the chelators and was reversible after removal of the
ligands. In contrast to the chelators, the Fe(III) complexes of DFO and
311 had no effect on increasing GADD45 and WAF1 mRNA levels, suggesting
that Fe chelation was required. Finally, the increase in GADD45 and
WAF1 mRNAs appeared to occur by a p53-independent pathway in SK-N-MC
and K562 cells, because these cell lines lack functional p53. Our
results suggest that GADD45 and WAF1 may play important roles in the
cell cycle arrest observed after exposure to these chelators.
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