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Abstract
Abstract Background: NAD+ kinase (NADK) is at present the only known enzyme that converts NAD+ to NADP+, which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein and fatty acid synthesis found in proliferating cells, as well as for neutralizing high levels of reactive oxygen species (ROS) present in these cells. The aim of this study was to determine whether inhibitors of NADK synergize with chemotherapeutic drugs known to induce ROS. Methods: Using a NADK inhibitor our group previously identified, thionicotinamide adenine dinucleotide phosphate (NADPS), (Mol Pharmacol., in press), we explored combinations of NADPS with various classes of drugs known to induce ROS: tubulin inhibitors (docetaxel, paclitaxel, vinblastine), a nucleoside analog (gemcitabine), topoisomerase I and II inhibitors (irinotecan and doxorubicin, respectively), and a DNA crosslinking agent (cisplatin). Fixed ratios of NADPS and the combination drug based on their EC50 values were tested in a colon cancer cell line (C85) using a MTS assay. The combination index (CI) was determined by the Chou-Talalay method for drug combination based on the median effect analysis. Results: All drugs were found to synergize with NADPS. Knockdown of NADK with siRNA or inhibition of NADK by NADPS in combination with MTX revealed equivalent efficacy. Quantification of intracellular NADPH and ROS levels are currently underway. Conclusions: NADK inhibitors along with drugs that increase ROS- mediated stress may represent an efficacious antitumor combination and should be explored further against in vivo tumor models. Citation Format: Philip M. Tedeschi, John Kerrigan, Debabrata Banerjee, Joseph R. Bertino, Emine E. Abali. NAD+ Kinase inhibition synergizes with ROS-inducing chemotherapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5536. doi:10.1158/1538-7445.AM2013-5536
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