A reactivity-based probe of the intracellular labile ferrous iron pool

Spangler, Benjamin; Morgan, Charles W.; Fontaine, Shaun D.; Wal, Mark N. Vander; Chang, Christopher J.; Wells, James A.; Renslo, Adam R.

doi:10.1038/nchembio.2116

Cited by 128 publications

(188 citation statements)

References 46 publications

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“…34 These initial studies with TRX-PURO also confirmed that labile iron pools are generally augmented in cancer cells when compared to nontumorigenic cells. 34 Our findings thus suggested that the TRX scaffold might indeed be applied to produce a novel class of TAPs for cancer chemotherapy.…”

Section: Introductionmentioning

confidence: 77%

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A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

et al. 2016

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Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics.

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Section: Introductionmentioning

confidence: 77%

“…This process occurs with high efficiency and ferrous-iron selectivity in mammalian cancer cell lines, as described recently. 34 …”

Section: Introductionmentioning

confidence: 99%

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

et al. 2016

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“…The former can be detected using inductively coupled plasma-MS or calcein AM quenching, as well as other specific iron probes (Hirayama and Nagasawa, 2017; Spangler et al, 2016), while the latter can be detected using phosphatidylcholine hydroperoxide reduction in cell lysates using LC-MS (Yang et al, 2014). …”

Section: Commonly Used Reagents For Studying Ferroptosismentioning

confidence: 99%

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Stockwell

Angeli

Bayır

et al. 2017

Cell

4,785

4,352

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Summary Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and that cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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“…In ICL-1, we caged D-aminoluciferin with an Fe 2+ -reactive endoperoxide trigger (15,17,51) inspired by antimalarial agents that exhibit Fe 2+ -dependent pharmacology (52,53). ICL-1 was designed to undergo metal-and redox-specific Fe 2+ -dependent cleavage to generate D-aminoluciferin, which can interact with the firefly luciferase enzyme to produce red light output through a catalytic bioluminescent reaction.…”

Section: Significancementioning

confidence: 99%

“…In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for detection by traditional recognition-based approaches (14), and as such we (15)(16)(17) and others (18)(19)(20) have pursued activity-based sensing approaches to detect labile Fe 2+ stores in cells (21)(22)(23)(24)(25). These tools have already provided insights into iron biology, as illustrated by the direct identification of elevations in LIPs during ferroptosis (26,27), an emerging form of cell death, using the ratiometric iron indicator FIP-1 (15).…”

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confidence: 99%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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A reactivity-based probe of the intracellular labile ferrous iron pool

Cited by 128 publications

References 46 publications

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

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