Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells

Horn, Adolfo; Fernandes, Christiane; Parrilha, Gabrieli L.; Kanashiro, Milton; Borges, Franz Viana; Melo, Édesio José Tenório de; Schenk, Gerhard; Terenzi, Hernán; Pich, Claus Tröger

doi:10.1016/j.jinorgbio.2013.07.019

Cited by 21 publications

(12 citation statements)

References 52 publications

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“…13,14 Iron-induced mitochondrial damage could be initiated either by intrinsic (caspase-9) or extrinsic (caspase-8) pathways that finally activate caspase-3, which is central for cell apoptosis. 56 In agreement with these reports, our results showed marked elevations in the markers of oxidative stress and renal cell apoptosis that were more pronounced in the acute than chronic intoxication. In addition, there was a marked decline in the levels of renal GPX4, a well-established marker of ferroptosis.…”

Section: Discussionsupporting

confidence: 92%

Acute and Chronic Iron Overloading Differentially Modulates the Expression of Cellular Iron-homeostatic Molecules in Normal Rat Kidney

Refaat

Abdelghany

BaSalamah

et al. 2018

J Histochem Cytochem.

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Little is known about the renal responses to acute iron overloading. This study measured the renal tubular expression of transferrin receptor-1 (TfR1), cubilin/megalin receptors, hepcidin, ferroportin, and ferritin chains following subacute intoxication of 40 male Wistar rats with a single oral dose of ferrous iron (300 mg/kg). The animals were randomly subdivided into 4 equal subgroups at the time of necropsy (1, 2, 4, and 8 hr). The results were compared with the controls ( n=15) and with the chronic group ( n=15), which received iron for 4 weeks (75 mg/kg/day; 5 days/week). Although both toxicity models inhibited TfR1, they upregulated the cubilin/megalin receptors and hepcidin, and triggered iron deposition in tubular cells. The ferritin heavy-chain and ferroportin were downregulated in the 2-hr and 4-hr acute subgroups, whereas chronic toxicity promoted their expression, compared with controls. Moreover, the 4-hr and 8-hr subgroups had higher intracellular Fe and marked cell apoptosis compared with the chronic group. In conclusion, the kidney appears to sustain iron reabsorption in both intoxication models. However, the cellular iron storage and exporter proteins were differentially expressed in both models, and their inhibition post-acute toxicity might contribute toward the intracellular accumulation of Fe, oxidative stress, and ferroptosis.

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Section: Discussionsupporting

confidence: 92%

Acute and Chronic Iron Overloading Differentially Modulates the Expression of Cellular Iron-homeostatic Molecules in Normal Rat Kidney

Refaat

Abdelghany

BaSalamah

et al. 2018

J Histochem Cytochem.

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“…Our results demonstrate that the iron(III) compound had low toxicity to LLC-MK2 host cells, which is consistent with previous results obtained using normal human peripheral blood mononuclear cells (16). However, the compound had an IC 50 of 3.6 mol liter Ϫ1 , which is notably lower than the values described in the literature for currently used clinical drugs.…”

Section: Discussionsupporting

confidence: 91%

“…This same compound and its dinuclear counterparts [Fe(HPCINOL)(SO 4 )] 2 --oxo and [Fe (HPCINOL)Cl] 2 --oxo accelerated DNA hydrolysis approximately 10 8 -fold compared to the spontaneous DNA cleavage rate, revealing impressive nuclease activity. However, the activities of these compounds against cancer cells were modest and associated with very low toxicity for normal human peripheral blood mononuclear cells (16). This lack of toxicity for normal cells prompted us to evaluate the activity of these compounds in antiparasitic therapies, because the main challenge of these therapies is the preservation of host cell viability.…”

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confidence: 99%

Reduction of Toxoplasma gondii Development Due to Inhibition of Parasite Antioxidant Enzymes by a Dinuclear Iron(III) Compound

Portes

Souza

Santos

et al. 2015

Antimicrob Agents Chemother

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g Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular protozoan that can infect a wide range of vertebrate cells. Here, we describe the cytotoxic effects of the dinuclear iron compound [Fe(HPCINOL)(SO 4 )] 2 --oxo, in which HPCINOL is the ligand 1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol, on T. gondii infecting LLC-MK2 host cells. This compound was not toxic to LLC-MK2 cells at concentrations of up to 200 M but was very active against the parasite, with a 50% inhibitory concentration (IC 50 ) of 3.6 M after 48 h of treatment. Cyst formation was observed after treatment, as indicated by the appearance of a cyst wall, Dolichos biflorus lectin staining, and scanning and transmission electron microscopy characteristics. Ultrastructural changes were also seen in T. gondii, including membrane blebs and clefts in the cytoplasm, with inclusions similar to amylopectin granules, which are typically found in bradyzoites. An analysis of the cell death pathways in the parasite revealed that the compound caused a combination of apoptosis and autophagy. Fluorescence assays demonstrated that the redox environment in the LLC-MK2 cells becomes oxidant in the presence of the iron compound. Furthermore, a reduction in superoxide dismutase and catalase activities in the treated parasites and the presence of reactive oxygen species within the parasitophorous vacuoles were observed, indicating an impaired protozoan response against these radicals. These findings suggest that this compound disturbs the redox equilibrium of T. gondii, inducing cystogenesis and parasite death.

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“…The tumor cell lines were treated with the morin compound (400 µM) and incubated for 36 hours at 37 °C under 5% CO 2 (Horn et al 2013). The results were obtained using FACSCalliburTM flow cytometer (BD Biosciences) and the data were analyzed using WinMDI software version 2.9.…”

Section: Analysis Of Mitochondrial Membrane Potential (δψM) By Flow C...mentioning

confidence: 99%

Morin exhibits leukemic cellular apoptosis through caspase pathway

Pereira

Oliveira

Kanashiro

et al. 2020

Natural Product Research

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The present study investigated the possibility of apoptosis-inducing activity in human leukemia U-937 and THP-1 cells by the flavonoid morin. The treatments were evaluated by using the MTT and LDH assays; analysis of mitochondrial membrane potential (ΔΨm) was evaluated by flow cytometry, cell death by apoptosis was confirmed by fluorescence microscopy and by assessing the activity of caspases-3 and -6. The data indicated that the flavonoid morin has promoted a decrease in cell viability in a concentration-dependent way for both of the cancerous cell lines. An increase in the percentage of cell death caused by apoptosis was associated to a potential alteration in the mitochondrial membrane (ΔΨm) suggesting the involvement of cell death in intrinsic apoptotic pathways. Activation of caspases-3 and -6 confirmed the presence of apoptotic activity from morin.The results reinforce the antileukemic potential of flavonol morin.

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Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells

Cited by 21 publications

References 52 publications

Acute and Chronic Iron Overloading Differentially Modulates the Expression of Cellular Iron-homeostatic Molecules in Normal Rat Kidney

Acute and Chronic Iron Overloading Differentially Modulates the Expression of Cellular Iron-homeostatic Molecules in Normal Rat Kidney

Reduction of Toxoplasma gondii Development Due to Inhibition of Parasite Antioxidant Enzymes by a Dinuclear Iron(III) Compound

Morin exhibits leukemic cellular apoptosis through caspase pathway

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