title: Gallium and its competing roles with iron in biological systems.
abstract: Gallium, a group IIIa metal, shares chemical properties with iron. Studies have shown that gallium-based compounds have potential therapeutic activity against certain cancers and infectious microorganisms. By functioning as an iron mimetic, gallium perturbs iron-dependent proliferation processes in tumor cells. Gallium's action on iron homeostasis leads to disruption of ribonucleotide reductase, mitochondrial function, and the regulation of transferrin receptor and ferritin. In addition, gallium nitrate stimulates an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Gallium's anti-infective activity against bacteria and fungi results from disruption of microbial iron utilization through mechanisms which include gallium binding to siderophores and downregulation of bacterial iron uptake. Gallium compounds lack cross-resistance to conventional chemotherapeutic drugs and antibiotics thus making them attractive agents for drug development. This review will focus on the mechanisms of action of gallium with emphasis on its interaction with iron and iron proteins.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA. Electronic address: chitambr@mcw.edu.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chitambar
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport; D004341:Drug Evaluation; D004354:Drug Screening Assays, Antitumor; D005708:Gallium / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005709:Gallium Isotopes / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009369:Neoplasms / Q000378:metabolism; D019159:Nonheme Iron Proteins / Q000378:metabolism; D051381:Rats; D014168:Transferrin / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D005709:Gallium Isotopes; D019159:Nonheme Iron Proteins; D014168:Transferrin; D005708:Gallium; D007501:Iron; C027235:gallium nitrate
keywords: Cancer; Gallium; Infection; Iron; Metallodrug therapeutics; Ribonucleotide reductase