Multifunctional antioxidant activity of HBED iron chelator

Samuni, Amram; Afeworki, Mobae; Stein, William; Yordanov, Alexander T.; DeGraff, William; Krishna, Murali C.; Mitchell, James B.; Brechbiel, Martin W.

doi:10.1016/s0891-5849(00)00459-7

Cited by 32 publications

(39 citation statements)

References 22 publications

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“…Tempol and TPH can modulate the conversion of the SQ in opposing directions and as such constitute a useful tool to study intracellular redox reactions (29,35). The observed sensitization of the 4-OHE 2 by Tempol and protection with TPH and other reducing agents (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…SQ radicals under aerobic conditions can either undergo oxidation to form the corresponding Q with concomitant generation of superoxide radical or be oxidized͞reduced by suitable oxidizing͞reducing agents. The ability of the SQ radical of 4-OHE 2 to oxidize substrates was tested by monitoring the conversion of the hydroxylamine TPH to the EPR-observable, stable nitroxide Tempol (29). Fig.…”

Section: Epr Studiesmentioning

confidence: 99%

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Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: Chemoprevention strategies with antioxidants

Samuni

Chuang

Krishna

et al. 2003

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

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Modulation of the cytotoxicity and mutagenicity of 4-hydroxyestradiol (4-OHE2), an oxidative metabolite of estrogen, by antioxidants was assessed in human MCF7 cells and TK-6 lymphoblast cells. The cytotoxicity of the catecholic estrogens was potentiated by depletion of intracellular glutathione and was independent of oxygen concentration. Agents such as the nitroxide Tempol can facilitate the oxidation of the semiquinone to the Q and enhanced 4-OHE2 cytotoxicity. Conversely, reducing agents such as ascorbate, cysteine, and 1,4-dihydroxytetramethylpiperidine (THP) protected against cytotoxicity and decreased mutation induction, presumably by reducing the semiquinone to the hydroquinone. Our results support the proposition that oxidation of the semiquinone to the corresponding Q is crucial in eliciting the deleterious effects of catecholic estrogens. Furthermore, because the deleterious effects of 4-OHE 2 were abrogated by dietary and synthetic antioxidants, our results would support the chemopreventive use of diets rich in reducing substances (vitamins and added synthetic antioxidants) as a means of decreasing the risks associated with estrogen exposure and developing of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Epr Studiesmentioning

confidence: 99%

Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: Chemoprevention strategies with antioxidants

Samuni

Chuang

Krishna

et al. 2003

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

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“…There are a range of Fe chelators that inhibit the reactions of Fe, oxygen, and their metabolites [140][141][142]. For instance, DFO markedly decreases the redox activity of Fe(III) [143] and is a very effective anti-oxidant via its ability to bind Fe [78].…”

Section: Redox Activity Of Fe Complexesmentioning

confidence: 99%

“…For instance, DFO markedly decreases the redox activity of Fe(III) [143] and is a very effective anti-oxidant via its ability to bind Fe [78]. Similarly, HBED has anti-oxidant activity, and like DFO, selectively binds Fe(III) thus preventing reduction of Fe(III) by superoxide and promoting auto-oxidation of Fe(II) [141].…”

Section: Redox Activity Of Fe Complexesmentioning

confidence: 99%

Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity

Chaston¹,

Richardson²

2003

American J Hematol

154

120

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The success of the iron (Fe) chelator desferrioxamine (DFO) in the treatment of ␤-thalassemia is limited by its lack of bioavailability. The design and characterization of synthetic alternatives to DFO has attracted much scientific interest and has led to the discovery of orally active chelators that can remove pathological Fe deposits. However, chelators that access intracellular Fe pools can be toxic by either inhibiting Fe-containing enzymes or promoting Fe-mediated free radical damage. Interestingly, toxicity does not necessarily correlate with Fe-binding affinity or with chelation efficacy, suggesting that other factors may promote the cytopathic effects of chelators. In this review, we discuss the interactions of chelators and their Fe complexes with biomolecules that can lead to toxicity and tissue damage. Am.

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“…There was no change in survival observed in the groups given RSV compared with control, and all mice were deceased by day 14 (data not shown). Additionally similar lethal-dose experiments were done in C3H mice using PIC (25,50 and 100 mg/kg; five mice per group) and showed no protection against 9 Gy TBI (data not shown). Since a 9 Gy dose resulted in no survival of mice with or without RSV or PIC pre-treatment, a lower sub-lethal IR dose of 6 Gy was evaluated with or without RSV pre-treatment (300 mg/kg; five mice per group).…”

Section: Resultsmentioning

confidence: 68%

The effects of resveratrol and selected metabolites on the radiation and antioxidant response

Fabre

Saito

DeGraff

et al. 2011

Cancer Biology & Therapy

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Excess reactive oxygen species (ROS) generated from ionizing radiation (IR) or endogenous sources like cellular respiration and inflammation produce cytotoxic effects that can lead to carcinogenesis. Resveratrol (RSV), a polyphenol with antioxidant and anticarcinogenic capabilities, has shown promise as a potential radiation modifier. The present study focuses on examining the effects of RSV or RSV metabolites as a radiation modifier in normal tissue. RSV or a RSV metabolite, piceatannol (PIC) did not protect human lung fibroblasts (1522) from the radiation-induced cell killing. Likewise, neither RSV nor PIC afforded protection against lethal total body IR in C3H mice. Additional research has shown protection in cells against hydrogen peroxide when treated with RSV. Therefore, clonogenic survival was measured in 1522 cells with RSV and RSV metabolites. Only the RSV derivative, piceatannol (PIC), showed protection against hydrogen peroxide mediated cytotoxicity; whereas, RSV enhanced hydrogen peroxide sensitivity at a 50 µM concentration; the remaining metabolites evaluated had little to no effect on survival. PIC also showed enhancement to peroxide exposure at a higher concentration (150 µM). A potential mechanism for RSV-induced sensitivity to peroxides could be its ability to block 1522 cells in the S-phase, which is most sensitive to hydrogen peroxide treatment. In addition, both RSV and PIC can be oxidized to phenoxyl radicals and quinones, which may exert cytotoxic effects. These cytotoxic effects were abolished when HBED, a metal chelator, was added. Taken together RSV and many of its metabolic derivatives are not effective as chemical radioprotectors and should not be considered for clinical use.

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Multifunctional antioxidant activity of HBED iron chelator

Cited by 32 publications

References 22 publications

Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: Chemoprevention strategies with antioxidants

Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: Chemoprevention strategies with antioxidants

Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity

The effects of resveratrol and selected metabolites on the radiation and antioxidant response

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