Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

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 (top2a). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2a 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. Antioxid. Redox Signal. 18, 930-955.

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

“…Pharmacologic reduction in mitochondrial iron using DXZ reduced Top-2β, consistent with previous reports (31,33,34), while DFO had no effect on Top-2β protein ( Figure 9D). However, genetic reduction in mitochondrial iron through adenoviral overexpression of ABCB8 in NRCMs ( Figure 9E) or TG expression of ABCB8 in mouse hearts ( Figure 9F) did not alter Top-2β protein, arguing that Top-2β function in DOX toxicity is independent of that of mitochondrial iron accumulation.…”

“…However, it remains unclear how Top-2β and mitochondrial iron pathways relate to each other in their modulation of DOX-induced cardiac damage. There may be a yet unidentified link between mitochondrial iron homeostasis and topoisomerases, as several iron chelators, including DXZ, were also shown to inhibit Top-2α/2β activities (43). However, the protective effects reported here are likely independent of the topoisomerase pathway, since a topoisomerase-inactive analog of DXZ that retains its iron-chelating properties confers a similar degree of protection to its parent compound (44), and also genetic overexpression of ABCB8 confers protection comparable to that of DXZ.…”

“…Moreover, DXZ was previously shown to inhibit Top-2β (31,32), suggesting that, in addition to reducing mitochondrial iron, DXZ may protect the heart through Top-2β suppression. To determine whether there is interplay between mitochondrial iron and Top-2β pathways in mediating DOX toxicity, we first asked whether Top-2β is involved in mitochondrial iron regulation by DOX.…”

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

“…Furthermore, upregulated expression of CD71 is considered as a marker of poor prognosis in breast cancer patients [28]. Based on these and other relevant observations, iron chelation therapy has been proposed and tested in various forms of cancer [29][30][31][32][33] with mixed results regarding efficacy [34,35] and side effects [36]. One possible reason for the limited efficacy of iron chelation in cancer is that it mostly targets extracellular iron.…”

Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity

“…Doxorubicin (Dox) is the most common and effective anticancer anthracycline chemotherapeutic, but its dose-dependent chronic side effects, including cardiomyopathy and congestive heart failure, have limited its potential in clinical practice (2,3). The mechanism of Dox-induced cardiotoxicity is complex, but the most widely accepted hypothesis is based on the metal-catalyzed generation of ROS and oxidative damage to cardiac tissue (4,5). Dox-induced oxidative stress has been reported in all major organs (6-9); however, due to the low level of antioxidant defenses and high abundance of mitochondria in the heart compared with other tissues, the heart is a major target of mitochondrial and bioenergetic failure, leading to cell death by apoptosis (10).…”