Probing intercalation and conformational effects of the anticancer drug 2-methyl-9-hydroxyellipticinium acetate in DNA fragments with circular dichroism

Authors

  • Monique MONNOT,

    1. Institut Gustave Roussy, Laboratoire de Biochimie-Enzymologie, URA 147 Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Villejuif, France
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  • Olivier MAUFFRET,

    1. Institut Gustave Roussy, Laboratoire de Biochimie-Enzymologie, URA 147 Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Villejuif, France
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  • Elie LESCOT,

    1. Institut Gustave Roussy, Laboratoire de Biochimie-Enzymologie, URA 147 Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Villejuif, France
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  • Serge FERMANDJIAN

    Corresponding author
    1. Institut Gustave Roussy, Laboratoire de Biochimie-Enzymologie, URA 147 Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Villejuif, France
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Correspondence to S. Fermandjian, Institut Gustave Roussy, Laboratoire de Biochimie-Enzymologie, PR II, F-94800 Villejuif Cedex, France

Abstract

Circular dichroism was applied to the analysis of drug-DNA associations. With the octanucleotide d(TGACGTCA) (octanucleotide I), which is the cAMP-responsive element (CRE) in gene promoters and its reverse d(ACTGCAGT) (octanucleotide II), it was demonstrated that the anticancer polyaromatic agent celiptium intercalates into DNA base pairs with its long direction perpendicular to both the DNA-helix axis and the base-pair long axis and induces larger conformational changes in the CpG-containing octanucleotide I CRE than in its reverse-sequence octanucleotide II.

It was concluded that CD is a powerful and sensitive technique to discriminate between drug-binding modes of DNA, to define the geometry of the chromophore inserted into base pairs and, finally, to measure sequence-dependent conformational changes induced by intercalation in DNA.

We anticipate that these studies will contribute to a better understanding of the molecular bases that underlie the mechanism of action of those cytotoxic drugs which interfere with the DNA-nuclear-protein recognition.

Abbreviations
NMHE

2-methyl-9-hydroxyellipticinium acetate

CRE

cAMP-responsive element

d(TGACGTCA)

octanucleotide I

d(ACTGCAGT)

octanucleotide II

Ancillary