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

Spangler, Benjamin; Fontaine, Shaun D.; Shi, Yihui; Sambucetti, Lidia; Mattis, Aras N.; Hann, Byron; Wells, James A.; Renslo, Adam R.

doi:10.1021/acs.jmedchem.6b01470

Cited by 35 publications

(35 citation statements)

References 49 publications

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“… 49 This reduction is consistent with studies on 1,2,4-trioxolanes and plakortin derivatives that suggest rapid reduction of the peroxide functionality. 34 , 35 , 49 , 50 Consistent with previous studies, artesunate ( 2 ) also decomposed after exposure to iron ( Supplementary Figure 11 ). 7 Inactive analogues 32 and 41 were only partially decomposed after iron exposure ( Supplementary Figure 11 ).…”

Section: Resultssupporting

confidence: 89%

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FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

et al. 2018

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Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc− or directly target GPX4, as do erastin and RSL3, respectively, or deplete GPX4 protein, as does FIN56. Instead, FINO2 causes both indirect loss of GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multi-pronged mechanism of ferroptosis.

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Section: Resultssupporting

confidence: 89%

“…Thus, the activity of FINO 2 could be due to the reduced product, as observed for some other peroxide-based drugs. 34 , 35 …”

Section: Resultsmentioning

confidence: 99%

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

et al. 2018

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“…Our design of ICL-1 involved caging D-luciferin with a 1,2,4-trioxolane scaffold (51) used previously for in vivo delivery of therapeutic payloads in an Fe 2+ -dependent manner (50,54). The excellent pharmacokinetic properties of these therapeutic conjugates suggested that ICL-1 would have suitable in vivo properties for the desired imaging applications.…”

Section: Resultsmentioning

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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113

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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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“…Similarly, SGT-94 uses the same targeted system to deliver a modified form of the retinoblastoma tumor suppressor gene, RB94, and has recently completed phase I assessment (NCT01517464). Another fascinating drug delivery mechanism involves a pro-drug strategy via trioxolane conjugation that reacts with ferrous iron in the tumor microenvironment to activate drug release (228). It is hoped that these delivery strategies will circumvent systemic toxicity and preliminary results seem promising.…”

Section: Targeting Iron Metabolism and Regulatory Mechanismsmentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

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Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

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

Cited by 35 publications

References 49 publications

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

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

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

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