Iron chelators in cancer therapy
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Iron chelators in cancer therapy Ola Ibrahim
. Jeff O’Sullivan
Received: 8 May 2020 / Accepted: 29 July 2020 Ó Springer Nature B.V. 2020
Abstract Iron chelators have long been a target of interest as anticancer agents. Iron is an important cellular resource involved in cell replication, metabolism and growth. Iron metabolism is modulated in cancer cells reflecting their increased replicative demands. Originally, iron chelators were first developed for use in iron overload disorders, however, their potential as anticancer agents has been gaining increasing interest. This is due, in part, to the downstream effects of iron depletion such as the inhibition of proliferation through ribonucleotide reductase activity. Additionally, some chelators form redox active metal complexes with iron resulting in the production of reactive oxygen species and oxidative stress. Newer synthetic iron chelators such as Deferasirox, Triapine and di-2-pyridylketone-4,4,dimethyl-3-thiosemicrbazone (Dp44mt) have improved pharmacokinetic properties over the older chelator Deferoxamine. This review examines and discusses the various iron chelators that have been trialled for cancer therapy including both preclinical and clinical studies. The successes and shortcomings of each of the chelators and their use in combination therapies are highlighted and future potential in the cancer therapy world is considered.
O. Ibrahim (&) J. O’Sullivan School of Dental Science, Dublin Dental University Hospital, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland e-mail: [email protected]
Keywords Iron Chelator Cancer Deferoxamine Deferasirox Triapine Dp44mt
Introduction Iron is essential for life, as it has an important role in many cellular processes including; oxygen transport (it forms part of haemoglobin which acts as an oxygen carrier), electron transport, and as a cofactor for several key enzymes involved in various cellular processes. For example; it acts as a cofactor for ribonucleotide reductase which catalyses the conversion of ribonucleotides into deoxyribonucleotides, the rate limiting step in DNA synthesis. Iron is also important for cell cycle progression as its subsequent depletion was found to cause hypophosphorylation of the retinoblastoma protein (pRb) and a decrease in the expression of cyclins A, B and D (Kulp et al. 1996). The catalytic ability relates to the presence of two forms of iron, Fe2? and Fe3? which it can cycle between and act both as an electron donor or acceptor. This ability to undergo cyclic oxidation and reduction is central to its function. However, this can result in the generation of reactive oxygen species (ROS) via the Fenton reaction. This reaction involves the reduction of H2O2 by Fe2? to produce the very reactive hydroxyl radical (OH) (Haber et al. 1934). Fe2þ þ H2 O2 þ Hþ ! Fe3þ þ H2 O þ OH
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Biometals
The oxidative stress arising from ROS production can damage a number of cell structures including lipids, membranes, proteins, and
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