title: Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy.
abstract: 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.
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Tedeschi
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
authors.forename: HongXia
authors.initials: H
authors.lastname: Lin
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Gounder
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
authors.forename: John E
authors.initials: JE
authors.lastname: Kerrigan
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
authors.forename: Emine Ercikan
authors.initials: EE
authors.lastname: Abali
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scotto
authors.affiliation: Departments of Pharmacology and Medicine, Rutgers Cancer Institute of New Jersey (P.M.T., H.L., M.G., J.E.K., K.S., J.R.B.), and Department of Biochemistry (E.E.A.), Rutgers University, New Brunswick, New Jersey bertinoj@cinj.rutgers.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009249:NADP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D009536:Niacinamide; D009249:NADP; C070820:thionicotinamide