Mechanisms of action of quinone-containing alkylating agents: DNA alkylation by aziridinylquinones

Hargreaves, Robert H J; Hartley, John A.; Butler, J. A. V.

doi:10.2741/hargreav

Cited by 58 publications

(29 citation statements)

References 42 publications

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“…We did note a time-dependent inactivation of reduced TrxR by aziridinylbenzoquinones and daunorubicin, but also this property was less efficient than what was reported earlier (31). Because these quinones are unable to react with cysteine or selenocysteine directly, the inactivation should have been due to alkylating reactions of their reduced products, the quinomethide of daunorubicin or aziridinyl-substituted hydroquinones (23,25). These may be formed during the TrxR-catalyzed reduction.…”

Section: Interaction Of Quinones With Mammalian Thioredoxin Reductasementioning

confidence: 55%

“…Such inhibition might be important in the cytotoxicity of the phenanthrene quinone compound, which is a component of exhaust gases and an important environmental pollutant (24). In relation to such inhibition, we find it important to note that we found the anticancer aziridinylbenzoquinones MeDZQ, RH1, and BZQ (23,25) as well as daunorubicin (Fig. 1) to be almost inactive as direct competitive inhibitors, in contrast to the efficient inhibition by these analogues of purified mammalian TrxR reported previously (31).…”

Section: Interaction Of Quinones With Mammalian Thioredoxin Reductasementioning

confidence: 58%

“…The antitumor, cytotoxic, and antiparasitic activities of clinically used quinones are mainly believed to stem from effects due to redox cycling of their free radical or hydroquinone states, derived from reduction by flavoenzymes, or from covalent modifications of DNA and other cellular nucleophiles (see Refs. [23][24][25]. Reduction of quinones by pyridine nucleotide-disulfide reductases related to TrxR, i.e.…”

mentioning

confidence: 99%

“…However, no systematic analysis of the reactions of quinones with mammalian TrxR has yet been performed. Here we examined the interactions of recombinant rat TrxR (32) with a number of structurally diverse quinones, including aziridinylbenzoquinones DZQ, RH1, MeDZQ, BZQ (25), anthracycline daunorubicin ( Fig. 1), and a number of model compounds for both partially and fully substituted quinones.…”

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confidence: 99%

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Interactions of Quinones with Thioredoxin Reductase

Čėnas¹,

Nivinskas²,

Anusevičius³

et al. 2004

Journal of Biological Chemistry

124

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Mammalian thioredoxin reductases (TrxR) are important selenium-dependent antioxidant enzymes. Quinones, a wide group of natural substances, human drugs, and environmental pollutants may act either as TrxR substrates or inhibitors. Here we systematically analyzed the interactions of TrxR with different classes of quinone compounds. We found that TrxR catalyzed mixed single-and two-electron reduction of quinones, involving both the selenium-containing motif and a second redox center, presumably FAD. Compared with other related pyridine nucleotide-disulfide oxidoreductases such as glutathione reductase or trypanothione reductase, the k cat /K m value for quinone reduction by TrxR was about 1 order of magnitude higher, and it was not directly related to the one-electron reduction potential of the quinones. A number of quinones were reduced about as efficiently as the natural substrate thioredoxin. We show that TrxR mainly cycles between the four-electron reduced (EH 4 ) and two-electron reduced (EH 2 ) states in quinone reduction. The redox potential of the EH 2 /EH 4 couple of TrxR calculated according to the Haldane relationship with NADPH/NADP ؉ was ؊0.294 V at pH 7.0. Antitumor aziridinylbenzoquinones and daunorubicin were poor substrates and almost inactive as reversible TrxR inhibitors. However, phenanthrene quinone was a potent inhibitor (approximate K i ‫؍‬ 6.3 ؎ 1 M). As with other flavoenzymes, quinones could confer superoxide-producing NADPH oxidase activity to mammalian TrxR. A unique feature of this enzyme was, however, the fact that upon selenocysteine-targeted covalent modification, which inactivates its normal activity, reduction of some quinones was not affected, whereas that of others was severely impaired. We conclude that interactions with TrxR may play a considerable role in the complex mechanisms underlying the diverse biological effects of quinones.Thioredoxin reductase (TrxR, 1 EC 1.8.1.9) catalyzes NADPHdependent reduction of the redox-active disulfide in thioredoxin (Trx), which serves a wide range of functions in cellular proliferation and redox control (1, 2). Thioredoxin reductases are homodimeric proteins that differ in properties between different classes of organisms. Low M r (34-kDa subunit) TrxRs of prokaryotes, plants, or yeast contain FAD and a redox-active disulfide/dithiol active site and display narrow substrate specificities. High M r (54 -58 kDa) TrxRs of animals have in contrast remarkably wide substrate specificities, explained by an additional easily accessible C-terminal redox center. This redox center is either a disulfide/dithiol as in TrxR of Plasmodium falciparum or Drosophila melanogaster or a selenocysteinecontaining selenenylsulfide/selenolthiol motif as found in TrxRs of mammals (3-6). In recent years, the catalytic mechanism of mammalian TrxR has been unraveled in significant detail. The three-dimensional crystal structure of rat TrxR is similar to that of glutathione reductase, including conserved FAD and NADP(H)-binding domains, but TrxR has a 16-residue C-term...

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Section: Interaction Of Quinones With Mammalian Thioredoxin Reductasementioning

confidence: 55%

Section: Interaction Of Quinones With Mammalian Thioredoxin Reductasementioning

confidence: 58%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Interactions of Quinones with Thioredoxin Reductase

Čėnas¹,

Nivinskas²,

Anusevičius³

et al. 2004

Journal of Biological Chemistry

124

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“…Further, a variety of alkylation reactions are observed, including Michael-type additions of sulfhydryl groups to quinones (4) or DNA alkylation (5). This biochemistry of quinones is exploited in cancer chemotherapy, such as with mitomycin c or certain anthraquinone derivatives including doxorubicin, yet the exact contributions of both redox and alkylation reactions to either the desired or adverse effects of these compounds are not fully elucidated.…”

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43

Abdelmohsen¹,

Gerber

Montfort

et al. 2003

Journal of Biological Chemistry

103

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Rat liver epithelial cells were exposed to three quinones with different properties: menadione (2-methyl-1,4-naphthoquinone, vitamin K 3 ), an alkylating as well as redox-cycling quinone, the strongly alkylating p-benzoquinone (BQ), and the non-arylating redox-cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). All three quinones induced the activation of extracellular signalregulated kinase (ERK) 1 and ERK 2 via the activation of epidermal growth factor receptor (EGFR) and MAPK/ ERK kinases (MEK) 1/2. ERK activation resulted in phosphorylation at Ser-279 and Ser-282 of the gap junctional protein, connexin-43, known to result in the loss of gap junctional intercellular communication. Another EGFRdependent pathway was stimulated, leading to the activation of the antiapoptotic kinase Akt via phosphoinositide 3-kinase. The activation of EGFR-dependent signaling by these quinones was by different mechanisms: (i) menadione, but not BQ or DMNQ, inhibited a protein-tyrosine phosphatase regulating the EGFR, as concluded from an EGFR dephosphorylation assay; (ii) although menadione-induced activation of ERK was unimpaired by pretreatment of cells with N-acetyl cysteine, activation by BQ and DMNQ was prevented; (iii) cellular glutathione (GSH) levels were strongly depleted by BQ. The mere depletion of GSH by application of diethyl maleate EGFR-dependently activated ERK and Akt, thus mimicking BQ effects. GSH levels were only moderately decreased by menadione and not affected by DMNQ. In summary, EGFR-dependent signaling was mediated by protein-tyrosine phosphatase inactivation (menadione), GSH depletion (BQ), and redox-cycling (DMNQ), funneling into the same signaling pathway.

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Antitumor Natural Products

Mitscher

Dutta

2003

Burger's Medicinal Chemistry and Drug Discovery

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The literature associated with major naturally occurring antitumor agents and related substances is reviewed and illustrated. Covered are dactinomycin, bleomycin, mitomycin, plicamycin, anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin, and valrubicin), camptothecins (topotecan and irinotecan), idopodophyllotoxins (etoposide and teniposide), taxus diterpenes (docetaxel and paclitaxel), and vinca dimeric alkaloids (vinblastine, vincristine, and vinorelbine).

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Mechanisms of action of quinone-containing alkylating agents: DNA alkylation by aziridinylquinones

Cited by 58 publications

References 42 publications

Interactions of Quinones with Thioredoxin Reductase

Interactions of Quinones with Thioredoxin Reductase

Epidermal Growth Factor Receptor Is a Common Mediator of Quinone-induced Signaling Leading to Phosphorylation of Connexin-43

Antitumor Natural Products

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