Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová, Marie; Rupertová, Martina; Schmeiser, Heinz H.; Frei, Eva

doi:10.5507/bp.2006.002

Cited by 65 publications

(76 citation statements)

References 61 publications

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“…However, the formation of ellipticine-DNA adducts, which is dependent on ellipticine activation by CYPs and peroxidases, has not yet been proven as a general mechanism. This ellipticine action was unambiguously found in vitro, using several CYP and peroxidase enzymes for ellipticine activation [3,17,19,21,24,45] and in vivo in rats and mice [8,22,24]. Ellipticine-DNA adducts were quantified also in three human cancer cell lines, breast adenocarcinoma MCF-7 cells [25], and the leukemia HL-60…”

Section: Discussionmentioning

confidence: 99%

“…The mode of antitumor, cytotoxic and mutagenic action of ellipticine is considered to be based mainly on DNA damage such as intercalation into DNA [4,44], inhibition of topoisomerase II [4,[14][15][16], and formation of covalent DNA adducts mediated by CYPs and peroxidases [3,19,21,24,45]. Intercalation of ellipticine into DNA and inhibition of topoisomerase II occur in all cell types irrespective of their metabolic capacity, because of the general chemical properties of this drug and its affinity to DNA and topoisomerase II protein [4,9,45]. However, the formation of ellipticine-DNA adducts, which is dependent on ellipticine activation by CYPs and peroxidases, has not yet been proven as a general mechanism.…”

Section: Discussionmentioning

confidence: 99%

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The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

Poljaková

Eckschlager

Hraběta

et al. 2009

Biochemical Pharmacology

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Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the appearance of DNA fragmentation, and in inhibition of cell growth. These effects were associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by the cytochrome P450-and peroxidase-mediated ellipticine metabolites, 13-hydroxy-and 12-hydroxyellipticine. The expression of these enzymes at mRNA and protein levels and their ability to generate ellipticine-DNA adducts in neuroblastoma cells were proven, using the real-time polymerase chain reaction, Western blotting analyses and by analyzing ellipticine-DNA adducts in incubations of this drug with neuroblastoma S9 fractions, enzyme cofactors and DNA. The levels of DNA adducts correlated with toxicity of ellipticine to IMR-32 and UKF-NB-4 cells, but not with that to UKF-NB-3 cells. In addition, hypoxic cell culture conditions resulted in a decrease in ellipticine toxicity to IMR-32 and UKF-NB-4 cells and this correlated with lower levels of DNA adducts. Both these cell lines accumulated in S phase, suggesting that ellipticine-DNA adducts interfere with DNA replication. The results demonstrate that among the multiple modes of ellipticine antitumor action, formation of covalent DNA adducts by ellipticine is the predominant mechanism of cytotoxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

Poljaková

Eckschlager

Hraběta

et al. 2009

Biochemical Pharmacology

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“…1), an alkaloid isolated from Apocynaceae plants, exhibits significant antitumor and anti-HIV activities [for a summary see [1][2][3]. The main reasons for the interest in ellipticine and its derivatives for clinical purposes are their high efficiencies against several types of cancer, their limited toxic side effects, and their lack of haematological toxicity [4].…”

Section: Introductionmentioning

confidence: 99%

Cytochrome b5 shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy

Kotrbová

Mrázová

Moserová

et al. 2011

Biochemical Pharmacology

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shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy. Biochemical Pharmacology, Elsevier, 2011, 82 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 45A c c e p t e d M a n u s c r i p A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 ABSTRACTEllipticine is a pro-drug, whose activation is dependent on its oxidation by cytochromes P450 (

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“…In both neuroblastoma cell lines treated with 10 μM ellipticine, almost 2-fold decrease in levels of ellipticine-DNA adducts by hypoxia was found and resulted from a decreased formation of adducts 1 and 2 in both types of cells 7 . This finding shows that CYP enzymes, whose activities are dependent on oxygen 13,14,33,34 , are predominantly responsible for formation of adducts 1 and 2 in these neuroblastoma cells 7 . A decrease in the levels of adducts 1 and 2 in neuroblastoma cells under hypoxic conditions corresponded to a decrease in toxicity of ellipticine under these conditions 7 .…”

Section: Cytotoxicity Of and Dna Adduct Formation By Ellipticine And mentioning

confidence: 86%

“…In addition, other mechanisms, such as intercalation into DNA (ref. 8 ), and inhibition of DNA topoisomerase II activity [8][9][10][11] resulting in ellipticine toxicity to neuroblastoma cannot be excluded (for a summary see [12][13][14][15] ). Of anthracycline antibiotics, doxorubicin ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Analysis of covalent ellipticine- and doxorubicin-derived adducts in DNA of neuroblastoma cells by the <sup>32</sup>P-postlabeling technique

Stiborová¹,

Poljaková²,

Eckschlager³

et al. 2012

BIOMED PAP

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eBackground. Ellipticine and doxorubicin are antineoplastic agents, whose action is based mainly on DNA damage such as intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts. The key target to resolve which of these mechanisms are responsible for ellipticine and doxorubicin anticancer effects is the development of suitable methods for identifying their individual DNA-damaging effects. Here, the 32 P-postlabeling method was tested to detect covalent DNA adducts formed by ellipticine and doxorubicin. Methods. The standard procedure of 32 P-postlabeling assay, this procedure under ATP-deficient conditions, the version using extraction of adducts with n-butanol and the nuclease P1 enrichment version were used to analyze ellipticineand/or doxorubicin-derived DNA adducts. Results. Two covalent ellipticine-derived DNA adducts, which are associated with cytotoxicity of ellipticine to human UKF-NB-3 and UKF-NB-4 neuroblastoma cell lines, were detected by the 32 P-postlabeling method. These adducts are identical to those formed by the ellipticine metabolites, 13-hydroxy-and 12-hydroxyellipticine. In contrast, no covalent adducts formed by doxorubicin in DNA of these neuroblastoma cells and in DNA incubated with this drug and formaldehyde in vitro were detectable by the 32 P-postlabeling assay. Conclusions. The results presented in this paper are the first to demonstrate that in contrast to covalent DNA adducts formed by ellipticine, the adducts generated by formaldehyde-mediated covalent binding of doxorubicin to DNA are not detectable by the 32 P-postlabeling assay. No DNA adducts were, detectable either in vitro, in incubations of DNA with doxorubicin or in DNA of neuroblastoma cells treated with this drug. The results also suggest that covalent binding of ellipticine to DNA of UKF-NB-3 and UKF-NB-4 neuroblastoma cell lines is the predominant mechanism responsible for the cytotoxicity of this drug. To understand the mechanisms of doxorubicin anticancer effects on neuroblastoma cells, development of novel methods for identifying covalent doxorubicin-derived DNA adducts is the major challenge for further research.

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Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Cited by 65 publications

References 61 publications

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

Cytochrome b5 shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy

Analysis of covalent ellipticine- and doxorubicin-derived adducts in DNA of neuroblastoma cells by the <sup>32</sup>P-postlabeling technique

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