Comment on Le and Richardson, page 2967

Iron chelation specifically up-regulates the N-myc downstream regulated gene 1 (Ndrg1), whose product is known to slow tumor growth and act as a potent metastasis suppressor.

Iron is a precious metal for the organism because of its unsurpassed versatility as a biologic catalyst; it is an essential component of virtually all organisms. The requirement for iron in tissue culture media has been known for more than 50 years but probably the first convincing evidence, demonstrating that iron plays a crucial role in DNA synthesis, was provided by Robbins and Pederson in 1970.1  They showed the presence of iron in a nuclear fraction and reported significant inhibition of DNA synthesis in HeLa cells by the iron chelator desferrioxamine. This has been confirmed and elaborated in various cell types using not only desferrioxamine but also many other iron chelating agents. Numerous studies have shown that iron limitation arrests cells in the G1 phase of the cell cycle but there are reports indicating that the progression of cells through S phase and perhaps beyond is iron dependent.2,3 

One plausible link between iron and cell proliferation is the enzyme ribonucleotide reductase, which produces the 4 deoxyribo-nucleotides from the corresponding ribonucleotides (the rate-limiting reaction in the synthesis of DNA precursors and, therefore, a key control point in DNA synthesis). In mammalian cells, the enzyme is composed of 2 nonidentical protein subunits: R1, the catalytic subunit that binds ribonucleotides; and R2, which requires Fe(III) for the stabilization of a tyrosyl radical. Inhibitors of ribonucleotide reductase block DNA syn thesis and cell replication; one such inhibitor is the iron chelator desferrioxamine, which is thought to act by withholding iron from the nonheme iron subunit of the enzyme. In addition to this “nutritional” requirement of proliferating cells for iron, this metal seems to play some kind of a “signaling” role in the cell cycle: iron chelators were shown to decrease levels of several cyclins in various tumor cell lines.3 

In this issue of Blood, Le and Richardson report an interesting and potentially important observation that provides evidence for a novel link between iron metabolism and cell growth. To assess the role of iron in cell cycle progression, the authors exploited gene arrays and examined the effects of 2 chelators, “classical” desferrioxamine and 2-hydroxy-1-naphthylaldehyde isonicotinonyl hydrazone (dubbed “311”), which was previously shown to have a remarkable antiproliferative activity,4  in comparison with those of the DNA-damaging agent actinomycin D. As expected, based on the previous work of Gao and Richardson,5  both chelators increased WAF1 (wild-type p53-activated fragment 1) and GADD45 (growth arrest and DNA damage genes) mRNA levels, 2 messages that were also elevated in actinomycin D-treated cells. However, both chelators, but not actinomycin D, also dramatically increased levels of mRNA for Ndrg1 (N-myc downstream-regulated gene 1); hence, the up-regulation of this gene is specifically linked to iron deprivation. Although the function of Ndrg1 is unknown, its overexpression was previously shown to markedly decrease tumor growth and inhibit metastasis. Considering this, the study of Le and Richardson has not only revealed a novel link between iron and cell proliferation but also suggests that chelator-mediated induction of Ndrg1 should be explored as a strategy to control tumor cell growth.

Robbins E, Pederson T. Iron: its intracellular localization and possible role in cell division.
Proc Natl Acad Sci U S A
Kühn LC, Schulman HM, Ponka P. Iron-transferrin requirements and transferrin receptor expression in proliferating cells. In: Ponka P, Schulman HM, Woodworth RC, eds.
Iron Transport and Storage
. Boca Raton, FL: CRC Press;
Le NT, Richardson DR. The role of iron in cell cycle progression and the proliferation of neoplastic cells.
Biochim Biophys Acta
Richardson DR, Tran EH, Ponka P. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents.
Gao J, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective anti-proliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression.