TY - JOUR T1 - Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy JF - Molecular Pharmacology JO - Mol Pharmacol SP - 720 LP - 727 DO - 10.1124/mol.114.096727 VL - 88 IS - 4 AU - Philip M. Tedeschi AU - HongXia Lin AU - Murugesan Gounder AU - John E. Kerrigan AU - Emine Ercikan Abali AU - Kathleen Scotto AU - Joseph R. Bertino Y1 - 2015/10/01 UR - http://molpharm.aspetjournals.org/content/88/4/720.abstract N2 - 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). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either small-hairpin RNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced the 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. ER -