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Review
. 2013 Mar 10;18(8):930-55.
doi: 10.1089/ars.2012.4877. Epub 2012 Oct 26.

Iron chelators with topoisomerase-inhibitory activity and their anticancer applications

V Ashutosh Rao  1
Affiliations
Review

Iron chelators with topoisomerase-inhibitory activity and their anticancer applications

V Ashutosh Rao. Antioxid Redox Signal. .

Abstract

Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents.

Recent advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2α). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2α inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome.

Critical issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review.

Future directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed.

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Figures

FIG. 1.
FIG. 1.
Currently understood mechanism for the iron-mediated generation of ROS by doxorubicin. The anthracycline doxorubicin undergoes a one-electron reduction of the C ring, leading to the formation of a semiquinone free radical metabolite. In the presence of oxygen, its unpaired electron is donated to oxygen forming superoxide radicals. Flavoproteins and glutathione (GSH/GSSG) catalyze the formation of a reduced semiquinone by accepting electrons from NADH or NADPH. SOD can catalyze the dismutation of superoxide into oxygen and H2O2 and provide an antioxidant defense, along with catalase and other antioxidant enzymes. A detailed description of the Fenton and Haber–Weiss reactions and the pathways labeled as Mechanism I or II are provided in the text. The iron-mediated generation of hydroxyl radicals can damage lipids, proteins, and DNA. The outcome of oxidative damage on critical cellular components could include apoptosis, autophagy, and/or necrosis. Modified with permission from Thomas Simunek (Charles University in Prague) (237). GSH, glutathione; GSSG, oxidized glutathione; H2O2, hydrogen peroxide; NADH, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; SOD, superoxide dismutase.
FIG. 2.
FIG. 2.
Chemical structures of dexrazoxane (ICRF-187), its iron-chelating metabolite ADR-925, and EDTA. After diffusing into cells, dexrazoxane is hydrolyzed by sequential ring openings via the catalytic actions of DHPase and DHOase enzymes. DHPase acts specifically on dexrazoxane as the first step. The structure of iron-chelating EDTA is provided as a comparison to ADR-925. DHOase, dihydroorotase; DHPase, dihydropyrimidinase; EDTA, ethylenediaminetetraacetic acid.
FIG. 3.
FIG. 3.
Chemical structures of the DpT family of iron chelators. The structural development of the pyridoxal isonicotinoyl hydrazone iron chelators led to the development of the DpT analogs. Among the analogs, Dp44mT showed iron chelating, top2α poisoning, and anticancer activity. DpT, di-2-pyridylketone thiosemicarbazone; Dp44mT, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone.
FIG. 4.
FIG. 4.
Potential sites of top2 inhibition by doxorubicin, dexrazoxane and Dp44mT. This schematic shows the currently understood processing of double-stranded DNA by the dimeric top2. Doxorubicin can block the catalytic cycle of the topoisomerase at either DNA ligation (before step 1) and/or DNA binding by interfering with top2 binding to DNA (between steps 4 and 5). Dexrazoxane blocks ATP hydrolysis and inhibits the reopening of the ATPase domain, thereby trapping the topoisomerase complex on DNA (between steps 5 and 6). While Dp44mT can trap top2α complex on DNA, further studies are needed to confirm the role of Fe2+ at other sites either on the ATPase domain or during ligation. Modified with permission from Yves Pommier (NIH/NCI) (201). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.)
FIG. 5.
FIG. 5.
Mechanism of processing of the top2 cleavage complex with DNA by topoisomerase inhibitors. Either by encountering a replication fork or being sensed by RNA/DNA polymerases, the top2 covalent complexes are recognized and processed for repair by at least two pathways. Proteolytic processing of the top2 dimer could occur using the ubiquitin/26 S proteosome, or by SUMOylation. The enzyme is partially detached from the DNA but not completely removed. Other enzymes that are capable of cleaving remaining phosphotyrosyl bonds to DNA such as Tdp1/2 could assist in removal from DNA. Alternatively, nucleases such as members of the Rad family of nucleases can sever the link with DNA, generating a single- or double-stranded break. The single-stranded break could be converted to a double-stranded break during further processing or by encountering a replication fork. Homologous recombination or nonhomologous end joining can attempt to repair the double-strand breaks generated, but the exact mechanism is still being investigated. Modified with permission from John Nitiss (University of Illinois) (185). Tdp, tyrosyl DNA phosphodiesterase.
FIG. 6.
FIG. 6.
Possible mechanisms of action by iron chelators that poison topoisomerases. Agents such as doxorubicin, dexrazoxane, and Dp44mT likely exert their anticancer activity by a combination of biochemical effects on the labile iron pool and on topoisomerase-mediated DNA damage. The generation of excess ROS by chelating iron could accentuate the DNA damaging effects by the agent. The oxidative damage of proteins and lipids also likely contributes to the cytotoxicity by excess ROS. Please refer to the text for an explanation of the possible pathways by which chelating iron and DNA damage could interplay. Top-DNA cc, topoisomerase DNA cleavage complex.
FIG. 7.
FIG. 7.
Proposed mechanism of divalent metal interaction with top2α. The amino acids on top2α (in green or blue) postulated to interact with two divalent metal ions (denoted MA2+ and MB2+) are shown (48, 51, 227). The DNA cleavage reaction has an absolute requirement for a divalent metal ion. Dewesse and Osheroff proposed that MA2+ stabilizes the transition state by making contacts with the 3′-bridging atom (red) and a nonbridging atom of the scissile phosphate (48). MB2+ is proposed to be required for DNA scission by providing anchoring and connects with the nonbridging oxygen of the phosphate that contacts the −1 and −2 bases upstream from the scissile bond (227, 239). While Mg2+ appears to fulfill this function in most studies, other metal ions such as Mn2+, Ca2+, and Co2+ can support double-stranded DNA cleavage in vitro (48, 50, 51). Please refer to the text for a discussion on the hypothetical potential for other metal ions, including Fe2+, to interact with top2α and/or DNA. Reproduced with permission from Niel Osheroff (Vanderbilt University) and Macmillan Publishers Ltd. (Nature) (51, 227). To see this illustration in color, the reader is referred to the web version of this article at www.liebertonline.com/ars.
FIG. 8.
FIG. 8.
Biomarkers for further studies on iron chelation and topoisomerase inhibition. Some of the biochemical causes and cellular consequences of iron-mediated ROS increase and DNA damage in cancer cells could be probed as illustrated in the diagram. The protein, lipid, and DNA mediators of cellular damage and the cellular outcomes of apoptosis, autophagy, and necrosis can be assayed using the endpoints that are shown adjacent to each step in the mechanism. A brief description of each of these assays is provided in the accompanying text. 8-oxoG, 7′,8′-dihydro-8-oxoguanine; AM, acetomethoxy derivative; DCFH-DA, 2′,7′-dichlorfluorescein-diacetate; HPLC, high performance liquid chromatography; ICE, immune complex with enzyme; LC3, microtubule-associated light chain protein; γ-H2AX, serine 139 phosphorylated histone H2A.
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