Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

Philip M. Tedeschi, Hong Xia Lin, Murugesan Gounder, John E. Kerrigan, Emine Ercikan Abali, Kathleen Scotto, Joseph R. Bertino

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

NAD1 kinase (NADK) is the only known cytosolic enzyme that converts NAD1 to NADP1, 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.

Original languageEnglish (US)
Pages (from-to)720-727
Number of pages8
JournalMolecular pharmacology
Volume88
Issue number4
DOIs
StatePublished - Oct 1 2015

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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