ABSTRACT
The lipid-soluble iron chelator desferri-exochelin (D-Exo) causes reversible cell cycle arrest in normal human mammary epithelial cells (NHMEC) but triggers apoptotic cell death in human breast cancer cells. We studied the effects of iron chelation with D-Exo on cell cycle regulatory proteins in cultures of NHMEC and MCF-7 breast cancer cells. In co-immunoprecipitation studies, D-Exo inhibited binding of cyclins A and E to cyclin dependent kinase 2 (CDK2) in NHMEC, but in MCF-7 cells binding of these cyclins to CDK2 was enhanced. D-Exo treatment markedly increased expression of p53 and increased binding of p21 to CDK2 in the MCF-7 cells but not in NHMEC. Therefore differences in effects of iron chelation on cell cycle protein binding in cancer cells compared to normal cells may trigger apoptosis in cancer cells while normal breast cells are spared.
Subject(s)
Breast Neoplasms/metabolism , Breast/metabolism , Cell Cycle Proteins/drug effects , Iron Chelating Agents/pharmacology , Peptides, Cyclic/pharmacology , Apoptosis/drug effects , Breast/cytology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Female , Humans , Hypoxia-Inducible Factor 1/biosynthesis , Iron Chelating Agents/chemistry , Protein Binding/drug effects , Solubility , Tumor Suppressor Protein p53/metabolismABSTRACT
Iron is an essential micronutrient for the growth and function of all cells. It is, therefore, an attractive target for chemotherapeutic compounds. Numerous studies in vitro and in vivo provide evidence that iron chelators may be effective antitumor agents. Lipophilic iron chelators that are readily cell permeable and can bind intracellular iron stores may selectively kill cancer cells without damaging normal cells. In this review we discuss the role of iron in cellular processes and how these processes differ between normal and neoplastic cells. We also review the effects on normal and cancer cell growth of several lipophilic iron chelators.
Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Cell Membrane Permeability , Iron Chelating Agents/metabolism , Iron Chelating Agents/therapeutic use , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Humans , Iron/pharmacology , Iron Chelating Agents/chemistry , Neoplasms/pathologyABSTRACT
Endothelial cell (EC) and vascular smooth muscle cell (VSMC) interactions play critical roles in restenosis following vascular injury. We examined the effects of intracellular iron chelation on endothelial cell cycle progression and VSMC modulation of endothelial cell growth. A diffusible, lipid-soluble iron chelator that rapidly enters cells, desferri-exochelin 772SM (D-Exo), was studied in human endothelial cells and VSMCs. In both cell types D-Exo reversibly halted cell cycle progression from G0/G1 phase to S phase and from S phase to G2/M phase and increased expression of hypoxia-inducible factor 1alpha (HIF-1alpha). D-Exo increased secretion of vascular endothelial growth factor (VEGF), a downstream target of HIF-1alpha, in VSMCs, but there was no VEGF production in endothelial cells. D-Exo was 25-fold more potent than the lipid-insoluble iron chelator deferoxamine, which does not readily enter cells. Intracellular iron chelation with D-Exo directly inhibits endothelial cell growth but indirectly stimulates endothelial cell growth by increasing VEGF release by VSMCs.
