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Blood, 1 August 2001, Vol. 98, No. 3, pp. 842-850
NEOPLASIA
The potential of iron chelators of the pyridoxal isonicotinoyl
hydrazone class as effective antiproliferative agents, IV: the
mechanisms involved in inhibiting cell-cycle
progression
Jin Gao and
Des R. Richardson
From the Iron Metabolism and Chelation Group, The Heart
Research Institute, Sydney, New South Wales, Australia.
Some chelators of the pyridoxal isonicotinoyl hydrazone class
have antiproliferative activity that is far greater than
desferrioxamine (DFO). In this study, DFO was compared with one of the
most active chelators (311) on the expression of molecules that play
key roles in cell-cycle control. This was vital for understanding the
role of iron (Fe) in cell-cycle progression and for designing chelators to treat cancer. Incubating cells with DFO, and especially 311, resulted in a decrease in the hyperphosphorylated form of the retinoblastoma susceptibility gene product (pRb). Chelators also decreased cyclins D1, D2, and D3, which bind with cyclin-dependent kinase 4 (cdk4) to phosphorylate pRb. The levels of cdk2 also decreased
after incubation with DFO, and especially 311, which may be important
for explaining the decrease in hyperphosphorylated pRb. Cyclins A and
B1 were also decreased after incubation with 311 and, to a lesser
extent, DFO. In contrast, cyclin E levels increased. These effects were
prevented by presaturating the chelators with Fe. In contrast
to DFO and 311, the ribonucleotide reductase inhibitor hydroxyurea
increased the expression of all cyclins. Hence, the effect of chelators
on cyclin expression was not due to their ability to inhibit
ribonucleotide reductase. Although chelators induced a marked increase
in WAF1 and GADD45 mRNA transcripts, there was
no appreciable increase in their protein levels. Failure to translate
these cell-cycle inhibitors may contribute to dysregulation of the cell
cycle after exposure to chelators.
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