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

Samuni, Amram; Chuang, Eric Y.; Krishna, Murali C.; Stein, William; DeGraff, William; Russo, Angelo; Mitchell, James B.

doi:10.1073/pnas.0930078100

Cited by 66 publications

(53 citation statements)

References 35 publications

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“…It is imperative to probe whether the reductive recovery of 1 from 2 via an enzymecatalyzed NAD(P)H-dependent reduction in the brain would produce oxidative stress similarly to that of redox cycling between catechol estrogens-derived quinones and their corresponding semiquinones [44]. Such redox cycling is believed to be responsible, in part, for the carcinogenicity of estrogens [45].…”

Section: Hydrogen Peroxide Productionmentioning

confidence: 99%

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

et al. 2008

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Antioxidant action is an important component of the complex neuroprotective action of estrogens. Combining theoretical prediction and subsequent experimental confirmation by chemical and in vitro paradigms, this study focused on the mechanistic aspects of hydroxyl-radical scavenging by 17β-butoxy-1,3,5(10)-estratrien-3-ol, a synthetic derivative of 17β-estradiol with increased potency to inhibit lipid peroxidation and reduced affinity to estrogen-receptors compared to the endogenous hormone. In the process that acts as a "chemical shield," the phenolic A-ring turns into 10β-hydroxy-17β-butoxy-1,3,5(10)-estratrien-3-one, a non-aromatic para-quinol, upon capturing hydroxyl-radicals, which results in the complete loss of estrogen-receptor affinity and antioxidant activity. However, the parent compound is apparently recovered in brain tissue from this para-quinol via enzyme-catalyzed NAD(P)H-dependent reductive aromatization without causing oxidative stress. Taken together, our report argues for a previously unrecognized antioxidant cycle for synthetic estrogen-derived compounds.

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Section: Hydrogen Peroxide Productionmentioning

confidence: 99%

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

et al. 2008

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“…20,21 This may explain the enhancement in cell killing seen in normal human cells. To confirm this, HRP and H 2 O 2 were added to RSV or PIC in the presence of the Tempol-H. 22 Phenoxyl radicals generated from the HRP/ H 2 O 2…”

Section: Resultsmentioning

confidence: 99%

“…Phenoxyl radicals can react with one another to generate a more stable quinone that can interact with cellular constituents like DNA to cause additional cellular damage. 22 Thus, the formation of phenoxyl radicals and quinones most likely contribute to RSV and PIC cytotoxicity alone (data not shown), the enhancement of IR radiosensitivity (Fig. 1A) and enhancement of peroxide cytotoxicity (Fig.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

“…These quinones are more stable and have a longer halflife compared with their phenoxyl radical intermediates and can interact with cellular constituents like DNA to cause additional cellular damage. 22 The structure of the quinones produces a shift in the UV-visible spectrum, which can be monitored. The UV absorbance changes were monitored using the HRP and H 2 O 2 chemical reaction along with RSV or PIC.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

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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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“…The Pice-Cu(II) complex is able to undergo intramolecular electron transfer to form semiquinone radical anion and Cu(I). (4,37,38). In brief, the formation of the hydroxyl radical and the Cu(II)/Cu(I) redox cycle play a key role in inducing DNA damage.…”

Section: Discussionmentioning

confidence: 99%

DNA breakage induced by piceatannol and copper(II): Mechanism and anticancer properties

Yang

Dong

et al. 2012

Oncology Letters

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Abstract. Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene; Pice), found in a variety of plant sources including grapes, red wine, peanuts and rhubarb, is known as a metabolite and analog of Resveratrol (3,5,4'-trihydroxy-trans-stilbene; Res) and has higher bioactivity than Res. To explore the mechanism of DNA damage induced by Pice in the presence of copper (Cu) (II), gel electrophoresis, UV-visible spectroscopy, fluorescence spectroscopy and Fourier transform infrared spectroscopy were used. The results of gel electrophoresis demonstrated that the hydroxyl radical played a critical role in DNA cleavage. Spectroscopy confirmed that the mechanism of DNA cleavage induced by Pice-Cu(II) involves the Haber Weiss and Fenton reactions. Pice chelates with Cu(II) as a bidentate ligand, and the Pice-Cu(II) complex undergoes intramolecular electron transfer to form the semiquinone radical anion and Cu(I), which may be reoxidated by O 2 to form Cu(II) with hydroxyl radical generation. In brief, the formation of the hydroxyl radical and the Cu(II)/Cu(I) redox cycle play a key role in inducing DNA damage. In this process, Pice demonstrated pro-oxidant properties. Oxidative product(s) of Pice, semiquinone, was formed and Cu(I) was reoxidized to Cu(II). The redox cycling of copper generated reactive oxygen species, which induced DNA cleavage, the hallmark of cell apoptosis. The mechanism of DNA breakage induced by Pice-Cu(II) may be a significant pathway through which cancer cells are killed.

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

Cited by 66 publications

References 35 publications

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

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

DNA breakage induced by piceatannol and copper(II): Mechanism and anticancer properties

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