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ToxSci Advance Access published online on March 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi149
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received November 30, 2004
Accepted March 15, 2005

Carcinogenicity

DNA INTERACTION AND DUAL TOPOISOMERASE I AND II INHIBITION PROPERTIES OF THE ANTI-TUMOUR DRUG PRODIGIOSIN

Beatriz Montaner 1, Wilmar Castillo-Ávila 1, Marc Martinell 2, Rupert Öllinger 1, Joan Aymami 3, Ernest Giralt 2, and Ricardo Pérez-Tomás 1*

1 Departament de Biologia Cel·lular i Anatomia Patològica. Cancer Cell Biology Research Group. Universitat de Barcelona. Barcelona. Spain. E-08907
2 Departament de Química Orgànica. Universitat de Barcelona. Barcelona. Spain. E-08028
3 Departament d'Enginyeria Química, ETSEIB. Universitat Politècnica de Catalunya. Barcelona. Spain. E-08028

* To whom correspondence should be addressed.
Ricardo Pérez-Tomás, E-mail: rperez{at}ub.edu


  Abstract

Prodigiosin is a red pigment produced by Serratia marcescens with apoptotic activity. We examined the mechanism of action of this tripyrrole alkaloid, focusing on its interaction with DNA and its ability to inhibit both topoisomerase I and topoisomerase II. We also evaluated the DNA damage induced in cancer cell lines. Prodigiosin-DNA intercalation was analysed using a competition dialysis assay with different DNA base sequences. Topoisomerase I and II inhibition was studied in vitro by a cleavage assay, and in cultured cells, analysing its ability to form covalent complexes. Furthermore, we analysed DNA damage by pulse-field gel electrophoresis and by immunocytochemistry. AIF/phospho-H2AX (p-H2AX) double labeling by confocal microscopy was performed to determine the possible implication of AIF in the prodigiosin-DNA damage. Finally, we studied the ability of this drug to induce cooper-mediated DNA damage at different pH by a DNA cleavage assay. Our results demonstrate prodigiosin-DNA interaction in vitro and in cultured cells. It involves prodigiosin-intercalation, with some preference for the alternating base pairs but with no discrimination between AT or CG sequences, dual abolition of topoisomerase I and II activity and, as consequence, DNA cleavage. Prodigiosin-DNA damage is independent of the apoptosis inducing factor (AIF). Furthermore, we found that cooper-mediated cleavage activity is associated with the pH (6.8 rather than 7.4) and with the Cu2+ ion concentration. These results indicate that DNA is a therapeutic target for prodigiosin and could explain the apoptosis mechanism of action induced by this antineoplastic drug.

Keywords: DNA damage; prodigiosin; topoisomerase inhibition.
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Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3{beta} activity in human breast cancer cells
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[Abstract] [Full Text] [PDF]


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