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ORIGINAL ARTICLE

Modulation of Cellular Response to Cisplatin by a Novel Inhibitor of DNA Polymerase

Equipe Instabilité Génétique et Cancer, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte Recherche Centre National de la Recherche Scientifique 5089 (F.B., P.B., Y.C., J.P.C., A.B., J.S.H., C.C.), Centre de Recherche en Pharmacologie-Santé, Unité Mixte Recherche Centre National de la Recherche Scientifique/P. Fabre 2587 (M.K.), Centre de Criblage Pharmacologique, Unité Mixte Recherche Centre National de la Recherche Scientifique/P. Fabre 2646 (F.A.), and Chimie des Substances Naturelles Bioactives, Unité Mixte Recherche Centre National de la Recherche Scientifique/P. Fabre 2597 (C.L., B.D., G.M.), Institut de Sciences et Technologies du Médicament de Toulouse 3, Toulouse, France; and Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland (E.F.-H., U.H.)

Abstract

DNA polymerase (Pol ) 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 inhibitors after high throughput screening of 8448 semipurified natural extracts. In vitro, the selected molecules affect specifically Pol -mediated DNA synthesis compared with replicative extracts from cell nuclei. One of them, masticadienonic acid (MA), is particularly attractive because it perturbs neither the activity of the purified replicative Pol nor that of nuclear HeLa cell extracts. With an IC₅₀ value of 8 µM, MA is the most potent of the Pol inhibitors found so far. Docking simulation revealed that this molecule could substitute for single-strand DNA in the binding site of Pol by binding Lys35, Lys68, and Lys60, which are the main residues involved in the interaction Pol /single-strand DNA. Selected inhibitors also affect the Pol -mediated translesion synthesis (TLS) across cisplatin adducts; MA was still the most efficient. Therefore, masticadienonic acid sensitized the cisplatin-resistant 2008C13*5.25 human tumor cells. Our data suggest that molecules such as masticadienonic acid could be suitable in conjunction with cisplatin to enhance anticancer treatments.

Address correspondence to: Dr. Christophe Cazaux, Equipe Instabilité Génétique et Cancer, Institut de Pharmacologie et de Biologie Structurale, UMR CNRS no. 5089, 205 route de Narbonne, 31077 Toulouse cedex 04, France. E-mail: cazaux{at}ipbs.fr

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