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

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Abstract
DNA polymerase β (Pol β) 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 β inhibitors after high throughput screening of 8448 semipurified natural extracts. In vitro, the selected molecules affect specifically Pol β-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 δ nor that of nuclear HeLa cell extracts. With an IC50 value of 8 μM, MA is the most potent of the Pol β inhibitors found so far. Docking simulation revealed that this molecule could substitute for single-strand DNA in the binding site of Pol β by binding Lys35, Lys68, and Lys60, which are the main residues involved in the interaction Pol β/single-strand DNA. Selected inhibitors also affect the Pol β-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.