%0 Journal Article %A Philip M Tedeschi %A HongXia Lin %A Murugesan Gounder %A John E Kerrigan %A Emine Ercikan Abali %A Kathleen Scotto %A Joseph Bertino %T Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy %D 2015 %R 10.1124/mol.114.096727 %J Molecular Pharmacology %P mol.114.096727 %X NAD+ kinase (NADK) is the only known cytosolic 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). The aim of this study was to determine whether inhibition of NADK activity is a valid anti-cancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either shRNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further. %U https://molpharm.aspetjournals.org/content/molpharm/early/2015/08/06/mol.114.096727.full.pdf