The role of iron in cell cycle progression and the proliferation of neoplastic cells

Biochim Biophys Acta. 2002 Oct 2;1603(1):31-46. doi: 10.1016/s0304-419x(02)00068-9.


Iron (Fe) is an obligate requirement for life and it is well known that Fe depletion leads to G(1)/S arrest and apoptosis. These facts, together with studies showing that Fe chelators can inhibit the growth of aggressive tumours such as neuroblastoma, suggest that Fe-deprivation may be an important therapeutic strategy. To optimise the anti-proliferative effects of Fe chelators, the role of Fe in cell cycle control requires intense investigation. For many years, Fe chelators were known to prevent the activity of the R2 subunit of ribonucleotide reductase (RR) that catalyzes the conversion of ribonucleotides into deoxyribonucleotides (dNTPs) for DNA synthesis. In addition, Fe depletion may also inhibit the newly identified p53-inducible form of this molecule called p53R2. This protein has the same Fe-binding sites as found in R2, and its activity is thought to supply dNTPs for the critical process of DNA repair. Iron chelation also causes hypophosphorylation of the retinoblastoma protein (pRb) and decreases the expression of cyclins A, B and D, which are vital for cell cycle progression. Other regulatory molecules whose expression is affected by Fe depletion include p53 and hypoxia inducible factor-1alpha (HIF-1alpha). The levels of p53 increase following Fe chelation via the ability of HIF-1alpha to bind and stabilize p53. The activity of HIF-1alpha is controlled by an Fe-dependent enzyme known as HIF-alpha prolyl hydroxylase (PH). Chelation of Fe from this enzyme inhibits its activity, leading to stabilization of HIF-1alpha and the subsequent effects on downstream targets critical for angiogenesis and tumour growth. The levels of p53 may also increase after Fe chelation by phosphorylation of this protein at serine-15 and -37. This prevents the interaction of p53 with murine double minute-2 (mdm-2) and its degradation. Iron chelation also markedly increases the mRNA levels of the p53-inducible cyclin-dependent kinase (cdk) inhibitor, p21(WAF1/CIP1). Surprisingly, the increase in p21(WAF1/CIP1) mRNA was not reciprocated at the protein level, and this may result in cell cycle dysregulation. This review will focus on the molecular mechanisms induced following Fe chelation and the role of Fe in cell cycle progression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / metabolism
  • Clinical Trials, Phase II as Topic
  • DNA Damage
  • DNA-Binding Proteins / metabolism
  • Drug Delivery Systems
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, myc
  • Humans
  • Iron / metabolism
  • Iron / physiology*
  • Iron Chelating Agents / metabolism
  • Iron Chelating Agents / pharmacology*
  • Iron Chelating Agents / therapeutic use
  • Molecular Sequence Data
  • Pyridines / therapeutic use
  • RNA-Binding Proteins / metabolism
  • Ribonucleotide Reductases / chemistry
  • Ribonucleotide Reductases / metabolism
  • Thiosemicarbazones / therapeutic use
  • Transcription Factors / metabolism


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Iron Chelating Agents
  • PLAGL2 protein, human
  • Pyridines
  • RNA-Binding Proteins
  • Thiosemicarbazones
  • Transcription Factors
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • Iron
  • RRM2B protein, human
  • Ribonucleotide Reductases