Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production

Akam, Eman A.; Utterback, Rachel D.; Marcero, Jason R.; Dailey, Harry A.; Tomat, Elisa

doi:10.1016/j.jinorgbio.2017.12.016

Cited by 15 publications

(28 citation statements)

References 74 publications

(90 reference statements)

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“…According to our previous observation that tumor-associated MΦ adopt an iron releasing phenotype ( Figure 3D), we further established an in vitro setting to analyze the role of macrophagesecreted iron in conferring renal tumor cell growth ( Figure 5A). As previously published [41,42], IL-10 stimulation of primary human MΦ induced the release of iron into the supernatant measured by AAS ( Figure 5B). We next applied macrophage-conditioned supernatants to renal tumor cells CAKI-1 (Figure 5C,E) and 786-O ( Figure 5D,F) and observed enhanced proliferation ( Figure 5C,D) as well as tumor cell migration (Figure 5E,F) measured by xCELLigence in real-time upon stimulation with IL-10-conditioned media.…”

Section: Tumor Proliferation By Macrophage-secreted Iron Is Suppressesupporting

confidence: 83%

“…Macrophage iron homeostasis is functionally coupled to their heterogeneity and plasticity, with their polarization status being reflected also by their expression profiles of iron-regulated genes. We previously showed that treatment of MΦ with LPS/IFNγ enhanced the retention of iron within the cell, whereas stimulation with anti-inflammatory cytokines such as IL-10 or IL-4 induced the release of iron [41]. This observation falls in line with a typical cytokine/chemokine profile of differentially polarized MΦ.…”

Section: Discussionsupporting

confidence: 64%

“…Our previous studies using intracellularly active pro-chelators underscore the importance of macrophage-released iron for tumor cell proliferation [41]. Intriguingly, current research focuses primarily on the role of iron and iron-chelation therapy in tumor cells, whereas detailed knowledge on the crosstalk between tumor cells and tumor-associated MΦ as a possible source of iron is lacking.…”

Section: Discussionmentioning

confidence: 99%

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The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

Schnetz

Meier

Rehwald

et al. 2020

Cancers

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Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth.

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Section: Tumor Proliferation By Macrophage-secreted Iron Is Suppressesupporting

confidence: 83%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

Schnetz

Meier

Rehwald

et al. 2020

Cancers

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“…This difference in activity likely arises from electronic differences between the phenyl vs. methyl substituents of BSPTH vs BSMTH, something that has been observed in disulfide-bridged prochelators built on a similar scaffold. 31,43 Interestingly, the disulfide prochelators introduced by Tomat and coworkers are reductively-activated and create S,N,S or S,N,O iron chelators with interesting antiproliferative activity against cancer cells. 12,43 The boronate prochelators discussed here, on the other hand, are oxidatively activated and create O,N,O coordination spheres.…”

Section: Discussionmentioning

confidence: 99%

“…31,43 Interestingly, the disulfide prochelators introduced by Tomat and coworkers are reductively-activated and create S,N,S or S,N,O iron chelators with interesting antiproliferative activity against cancer cells. 12,43 The boronate prochelators discussed here, on the other hand, are oxidatively activated and create O,N,O coordination spheres. The combination of these two approaches reveals the opportunity available to tune prochelators for desirable biological applications by adjusting their coordination sphere, activation mechanism and stability.…”

Section: Discussionmentioning

confidence: 99%

Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress

Wang

Franz

2018

Bioorganic & Medicinal Chemistry

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BSIH ((E)-N’-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) is a prodrug version of the metal chelator SIH ((E)-N’-(2-hydroxybenzylidene)isonicotinohydrazide) in which a boronate group prevents metal chelation until reaction with hydrogen peroxide releases SIH, which is then available for sequestering iron(III) and inhibiting iron-catalyzed oxidative damage. While BSIH has shown promise for conditionally targeting iron sequestration in cells under oxidative stress, the yield of SIH is limited by the fact that BSIH exists in cell culture media as an equilibrium mixture with its hydrolysis products isoniazid and 2-formylphenyl boronic acid. In the current study, several BSIH analogs were evaluated for their hydrolytic stability, reaction outcomes with H2O2, and prochelator-to-chelator conversion efficiency. Notably, the para-methoxy derivative (p-OMe)BSIH ((E)-N’-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) and the meta-, para- double substituted (MD)BSIH ((E)-N’-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)methylene)isonicotinohydrazide) showed 1.3- and 1.9-fold improved hydrolytic stability compared to BSIH, respectively, leading to a 22 and 50 % increase in chelator released. Moreover, both prochelators were found to protect retinal pigment epithelial cells stressed with either H2O2 or paraquat insult.

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Developing Ligands to Target Transition Metals in Cancer

Utterback

Tomat

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Transition metals are essential for the function for numerous metalloproteins and cofactors in living systems. Their acquisition, transport, and storage are tightly regulated and the homeostasis of redox‐active cations such as iron and copper is especially critical to prevent the damaging effects of oxidative stress. Indeed the dyshomeostasis of metals has been observed in the pathophysiology of several diseases, and multiple metal‐binding compounds are currently under investigation as therapeutic candidates. Herein, we focus on the altered metal metabolisms of malignant cells and on metal‐binding strategies for the design of cancer chemotherapeutics. Iron, copper, and zinc chelators with a variety of binding motifs have been studied for their antiproliferative effects in malignant cells, and several compounds have reached clinical trials. Recent pro‐chelation approaches, in which the chelator is activated under specific conditions, are poised to increase therapeutic indexes and avoid unwanted side effects. As additional information emerges on the roles of metals in cancer biology, the design of metal‐binding drug candidates is evolving to improve their selectivity and efficacy and to consider their effects on the immune cells present in the tumor microenvironment. In addition, extensive studies to develop inhibitors of metalloenzymes relevant to cancer growth have led to several new anticancer therapeutics that coordinate the zinc centers in the active site of the enzymes. As illustrated by the examples collected herein, approaches that target either labile or protein‐bound transition metals have significant potential to produce new therapeutic options for cancer treatment.

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Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production

Cited by 15 publications

References 74 publications

The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

The Disturbed Iron Phenotype of Tumor Cells and Macrophages in Renal Cell Carcinoma Influences Tumor Growth

Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress

Developing Ligands to Target Transition Metals in Cancer

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