Peroxidase-catalyzed covalent binding of the antitumor drug N2-methyl-9-hydroxyellipticinium to DNA in vitro

Auclair, Christian; Dugue, Bernard; Meunier, Bernard; Paoletti, Claude

doi:10.1021/bi00354a007

Cited by 35 publications

(12 citation statements)

References 21 publications

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“…These compounds are oxidized to the quinone-imine which then undergoes regiospecific Michael-type addition of bionucleophiles at the 10-position of quinone-imine yielding and Potier's 62, 63 research groups. The non-hydroxylated ellipticine derivatives were found by these authors not to be oxidized and to bind only very weakly to DNA 54 . In contrast to these results, our studies indicate that ellipticine is easily and effectively oxidized by peroxidases to species that bind to DNA [28][29][30] .…”

Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 89%

“…Peroxidases expressed in some cancer cells might be good candidates for such ellipticine activation [42][43][44][45][46][47][48][49][50][51][52][53] . In the mid 1980s the group of B. Meunier studied binding of one radioactively labeled ellipticine derivative, the antitumour drug 9-hydroxy-N 2 -methylellipticinium to DNA or RNA upon oxidation by horseradish peroxidase (HRP) 5,[54][55][56] . They and others proposed a mechanism by which this and other 9-hydroxylated ellipticine derivatives 5,[54][55][56][57][58][59][60] can act as bioalkylating agents [60][61][62][63] .…”

Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 99%

“…In the mid 1980s the group of B. Meunier studied binding of one radioactively labeled ellipticine derivative, the antitumour drug 9-hydroxy-N 2 -methylellipticinium to DNA or RNA upon oxidation by horseradish peroxidase (HRP) 5,[54][55][56] . They and others proposed a mechanism by which this and other 9-hydroxylated ellipticine derivatives 5,[54][55][56][57][58][59][60] can act as bioalkylating agents [60][61][62][63] . These compounds are oxidized to the quinone-imine which then undergoes regiospecific Michael-type addition of bionucleophiles at the 10-position of quinone-imine yielding and Potier's 62, 63 research groups.…”

Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 99%

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Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

BIOMED PAP

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Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy-and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N 6 of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy-and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP-and peroxidase-mediated metabolite, ellipticine N 2 -oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

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Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 89%

Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 99%

Section: Oxidation Of Ellipticine By Peroxidases: Another Way To Metamentioning

confidence: 99%

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Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

BIOMED PAP

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“…In the mid 1980s, the group of B. Meunier studied binding of one radioactively labeled ellipticine derivative, the antitumor drug, 9‐hydroxy‐ N 2 ‐methylellipticinium to DNA or RNA upon oxidation by horseradish peroxidase (HRP) 2, 31, 32, 33. They and others proposed a mechanism by which this and other 9‐hydroxylated ellipticine derivatives2, 31, 32, 33, 34, 35, 36, 37 can act as bioalkylating agents 37, 38, 39, 40. These compounds are oxidized to the quinone‐imine, which then undergoes regiospecific Michael‐type addition of bionucleophiles at the 10‐position of quinone‐imine yielding the adduct product with nucleophiles.…”

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confidence: 99%

Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12‐hydroxyellipticine and 13‐hydroxyellipticine

Stiborová

Poljaková

Ryšlavá

et al. 2006

Intl Journal of Cancer

111

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Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation, inhibition of topoisomerase II and cytochrome P450-mediated formation of covalent DNA adducts. This is the first report on the molecular mechanism of ellipticine oxidation by peroxidases (human myeloperoxidase, human and ovine cyclooxygenases, bovine lactoperoxidase, horseradish peroxidase) to species forming ellipticine-DNA adducts. Using NMR spectroscopy, the structures of 2 ellipticine metabolites were identified; the major product is the ellipticine dimer, in which the 2 ellipticine skeletons are connected via N 6 of the pyrrole ring of one ellipticine molecule and C9 in the second one. The minor metabolite is ellipticine N 2 -oxide. Using 32 P-postlabeling and [ 3 H]-labeled ellipticine, we showed that ellipticine binds covalently to DNA after its activation by peroxidases. The DNA adduct pattern induced by ellipticine consisted of a cluster of up to 4 adducts. The 2 adducts are indistinguishable from the 2 major adducts generated between deoxyguanosine in DNA and either 13-hydroxy-or 12-hydroxyellipticine or in rats treated with ellipticine, or if ellipticine was activated with human hepatic and renal microsomes. The results presented here are the first characterization of the peroxidase-mediated oxidative metabolites of ellipticine and we have proposed species, 2 carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating 2 major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine. ' 2006 Wiley-Liss, Inc.Key words: ellipticine; anticancer drug; peroxidase; cytochrome P450; DNA adduct Ellipticine (5,carbazole), an alkaloid isolated from Apocyanaceae plants and several of its more soluble derivatives (9-hydroxyellipticine, 9-hydroxy-N 2 -methylellipticinium, 9-chloro-N 2 -methylellipticinium and 9-methoxy-N 2 -methylellipticinium) exhibit promising results in the treatment of osteolytic breast cancer metastases, kidney cancer, brain tumors and acute myeloblastic leukemia (for a summary see literature 1 ). The main reason for the interest in ellipticine and its derivatives for clinical purposes is their high efficiency against several types of cancer, their rather limited toxic side effects and their complete lack of hematological toxicity. 2 Nevertheless, ellipticine is a potent mutagen. Most ellipticines are mutagenic to Salmonella typhimurium Ames tester strains, bacteriophage T4, Neurospora crassa and mammalian cells and induce prophage lambda in Escherichia coli (for an overview see literature 1 ).The antineoplastic property of ellipticine was considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. 3-7 Recently, we found another mode of ellipticine action. 1,[8][9][10] We demonstrated that ellipticine covalently binds to DNA after being enzymatically activated. Using a panel of different human recombinant cytochrome...

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“…However, it was shown to act as an electron carrier and significantly increased oxygen consumption in rat liver microsomes-NADPH and xanthine oxidase-NADH systems, possibly indicating that reduction of the oxygen content of cells could be another mechanism adding to the toxicity of ellipticine derivatives. Auclair and Paoletti subsequently showed that if the ratio of quinine-imine:hydrogen peroxide is 1:1, then, in the presence of DNA, the quinone-imine 19 will react with the polynucleotide resulting in 9-hydroxy-2-methylellipticinium 3 covalently bound to DNA at intercalation sites, with a suggested linkage between C10 of 9-hydroxy-2-methylellipticinium and a primary amine in the DNA [57].…”

Section: Bioactivation Of Ellipticine Derivativesmentioning

confidence: 99%