Iron-targeting antitumor activity of gallium compounds and novel insights into triapine(®)-metal complexes. Antioxid Redox Signal 2013 Mar 10;18(8):956-72
Date
08/21/2012Pubmed ID
22900955Pubmed Central ID
PMC3557436DOI
10.1089/ars.2012.4880Scopus ID
2-s2.0-84873871117 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
SIGNIFICANCE: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents.
RECENT ADVANCES: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine(®) has demonstrated activity against other tumors.
CRITICAL ISSUES: Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed.
FUTURE DIRECTIONS: The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it.
Author List
Chitambar CR, Antholine WEMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Cell Proliferation
Coordination Complexes
Gallium
Humans
Iron
Iron Chelating Agents
Molecular Mimicry
Neoplasms
Pyridines
Thiosemicarbazones
