The oral iron chelator deferasirox inhibits <scp>NF</scp>‐κB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia

Banerjee, Aditi; Mifsud, Nicole A.; Bird, Robert; Forsyth, Cecily; Szer, Jeffrey; Tam, Constantine S.; Kellner, S.; Grigg, Andrew; Motum, Penelope; Bentley, Mark; Opat, Stephen; Grigoriadis, George

doi:10.1111/bjh.13151

Cited by 31 publications

(25 citation statements)

References 28 publications

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“…In addition, it has been shown that the oral Fe chelator deferasirox is able to inhibit NF- (nuclear factor-) kB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the hematopoietic improvement observed in deferasirox-treated patients affected by myelodysplasia and aplastic anemia might reflect an anti-inflammatory effect mediated through inhibition of the transcription factor NF-kB and support the therapeutic targeting of this pathway [37]. …”

Section: Chelating Agentsmentioning

confidence: 87%

Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals

Ferrero

2016

BioMed Research International

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Exposure to environmental and occupational toxicants is responsible for adverse effects on human health. Chelation therapy is the only procedure able to remove toxic metals from human organs and tissue, aiming to treat damage related to acute and/or chronic intoxication. The present review focuses on the most recent evidence of the successful use of the chelating agent ethylenediaminetetraacetic acid (EDTA). Assessment of toxic-metal presence in humans, as well as the rationale of EDTA therapy in cardiovascular and neurodegenerative diseases, is reported.

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Section: Chelating Agentsmentioning

confidence: 87%

Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals

Ferrero

2016

BioMed Research International

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“…Altered iron metabolism facilitates rapid proliferation in cancer cells [135]. Indeed, constitutive Wnt/β-catenin signaling in colon cancer cells is iron-dependent [136] and iron chelation limits cell proliferation and has anti-inflammatory effects through NF-κB blockade [137]. Iron overload causes DM and is present in target organs of diabetes, such as the kidneys, while iron depletion upregulates glucose uptake and insulin signaling in liver and decreases kidney inflammation in experimental diabetes [138–140].…”

Section: Potential Molecular Mechanisms Of the Association Between Dmmentioning

confidence: 99%

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

et al. 2017

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Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.

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“…Recent reports have shown that DFS not only has iron‐chelating properties but also additional biological effects, drawing the attention of several researchers to this agent. For example, DFS inhibits the proliferation of myeloid leukemia cells, nuclear transport of NF‐κB activation, and production of reactive oxygen species (ROS) …”

Section: Introductionmentioning

confidence: 99%

“…Recent reports have shown that DFS not only has iron-chelating properties but also additional biological effects, drawing the attention of several researchers to this agent. For example, DFS inhibits the proliferation of myeloid leukemia cells, 2,3 nuclear transport of NF-κB activation, 4,5 and production of reactive oxygen species (ROS). 6,7 Although neutrophil activation plays an important role in the immune system, redundant neutrophil activation can induce acute lung injury (ALI) as well as other pathologic conditions, owing to adhesion of activated neutrophils to vascular endothelial cells and ROS overproduction.…”

Section: Introductionmentioning

confidence: 99%

Iron‐chelating agent, deferasirox, inhibits neutrophil activation and extracellular trap formation

Kono

Saigo

Yamamoto

et al. 2016

Clin Exp Pharma Physio

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Iron-chelating agents, which are frequently prescribed to transfusion-dependent patients, have various useful biological effects in addition to chelation. Reactive oxygen species (ROS) produced by neutrophils can cause pulmonary endothelial cell damage, which can lead to acute lung injury (ALI). We previously reported that deferasirox (DFS), an iron-chelating agent, inhibits phorbol myristate acetate (PMA) or formyl-methionyl-leucyl-phenylalanine (fMLP)-induced ROS production in neutrophils, in vitro. Here, we investigate whether DFS inhibits vacuolization in neutrophils and neutrophil extracellular trap (NET) formation. Human neutrophils were incubated with DFS and stimulated with PMA or fMLP. Human neutrophils were separated from heparinized peripheral blood using density gradient centrifugation, and subsequently incubated with DFS. After 10 minutes, neutrophils were stimulated by PMA or fMLP. Vacuole formation was observed by electron microscopy. For observing NET formations using microscopes, immunohistological analyses using citrullinated histone H3 and myeloperoxidase antibodies, and SYTOX Green (an impermeable DNA detection dye) staining, were conducted. NET formation was measured as the quantity of double-stranded DNA (dsDNA), using the AccuBlue Broad Range dsDNA Quantitation Kit. DFS (50 μmol/L) inhibited vacuole formation in the cytoplasm and NET formation. Additionally, 5-100 μmol/L concentration of DFS inhibited the release of dsDNA in a dose-independent manner. We demonstrate that DFS inhibits not only ROS production but also vacuolization and NET formation in neutrophils. These results suggest the possibility of protective effects of DFS against NET-related adverse effects, including ALI and thrombosis.

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The oral iron chelator deferasirox inhibits NF‐κB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia

Cited by 31 publications

References 28 publications

Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals

Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

Iron‐chelating agent, deferasirox, inhibits neutrophil activation and extracellular trap formation

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