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ToxSci Advance Access originally published online on March 23, 2005
Toxicological Sciences 2005 85(2):870-879; doi:10.1093/toxsci/kfi149
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Toxicological Sciences vol. 85 no. 2 © 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

DNA Interaction and Dual Topoisomerase I and II Inhibition Properties of the Anti-Tumor Drug Prodigiosin

Beatriz Montaner*, Wilmar Castillo-Ávila*, Marc Martinell{dagger}, Rupert Öllinger*, Joan Aymami{ddagger}, Ernest Giralt{dagger} and Ricardo Pérez-Tomás*,1

* Departament de Biologia Cel·lular i Anatomia Patològica, Cancer Cell Biology Research Group, Universitat de Barcelona, Barcelona, Spain E-08907; {dagger} Departament de Química Orgànica, Universitat de Barcelona, Barcelona, Spain E-08028; {ddagger} Departament d'Enginyeria Química, ETSEIB, Universitat Politècnica de Catalunya, Barcelona, Spain E-08028

Received November 30, 2004; accepted March 15, 2005

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 analyzed 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, by analysis of its ability to form covalent complexes. Furthermore, we analyzed DNA damage by pulse-field gel electrophoresis and by immunocytochemistry. Apoptosis inducing factor (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 copper-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–DNA 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 AIF. Furthermore, we found that copper-mediated cleavage activity is associated with pH (occurring at pH 6.8 rather than pH 7.4) and with the Cu2+ ion concentration. These results indicate DNA a therapeutic target for prodigiosin and could explain the apoptosis mechanism of action induced by this antineoplastic drug.

Key Words: DNA damage; prodigiosin; topoisomerase inhibition.


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[Abstract] [Full Text] [PDF]


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