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First published on February 9, 2005; DOI: 10.1124/mol.104.001776

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Received for publication May 6, 2004.
Revised December 21, 2004.
Accepted for publication February 8, 2005.

Modulation of cellular response to cisplatin by a novel inhibitor of DNA polymerase {beta}

Francois Boudsocq 1, Pierre Benaim 1, Yvan Canitrot 1, Martine Knibiehler 1, Frederic Ausseil 2, Jean-Pascal Capp 1, Anne Bieth 3, Christophe Long 2, Bruno David 2, Igor Shevelev 4, Erika Frierich-Heinecken 4, Ulrich Hubscher 4, Francois Amalric 1, Georges Massiot 5, Jean-Sebastien Hoffmann 6, Christophe Cazaux 1*

1 IPBS CNRS 2 Pierre Fabre Company 3 IPBS CNR 4 Univ of Zurich 5 Pierre Fabre company 6 CNRS

* Address correspondence to: E-mail: cazaux{at}ipbs.fr

Abstract

DNA polymerase {beta}(Pol {beta}) is an error- prone enzyme whose up-regulation has been shown to be a genetic instability enhancer as well as a contributor to cisplatin resistance in tumor cells. In this work we describe the isolation of new Pol {beta} inhibitors after high throughput screening of 8,448 semi purified natural extracts. In vitro the selected molecules affect specifically Pol {beta}-mediated DNA synthesis as compared to replicative extracts from cell nuclei. One of them, masticadienonic acid (MA), is particularly attractive since it perturbs neither the activity of the purified replicative Pol {delta} nor that of nuclear HeLa cell extracts. With an IC50 value of 8 µ M, MA is the most potent of the Pol {beta} inhibitors known to-date. Docking simulation revealed that this molecule could substitute for single strand DNA in the binding site of Pol {beta} by binding Lys35, Lys68 and Lys 60 which are the main residues involved in the interaction Pol {beta}/single-strand DNA. Selected inhibitors also affect the Pol {beta}-mediated translesion synthesis across cisplatin adducts, MA being still the most efficient. As a consequence masticadienonic acid sensitised the cisplatin resistant 2008 C13*5.25 human tumour cells. Our data suggest that molecules such as masticadienonic acid could be suitable in conjunction with cisplatin to enhance anticancer treatments.


Key words: Structure-activity relationships and modeling, DNA damage and repair, Mechanisms of cell killing/apoptosis, Resistance


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