Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) activity by small molecule GMX1778 regulates reactive oxygen species (ROS)-mediated cytotoxicity in a p53- and nicotinic acid phosphoribosyltransferase1 (NAPRT1)-dependent manner.

The Journal of Biological Chemistry
David CernaStephen S Yoo

Abstract

Cancer cells undergo mitosis more frequently than normal cells and thus have increased metabolic needs, which in turn lead to higher than normal reactive oxygen species (ROS) production. Higher ROS production increases cancer cell dependence on ROS scavenging systems to balance the increased ROS. Selectively modulating intracellular ROS in cancers by exploiting cancer dependence on ROS scavenging systems provides a useful therapeutic approach. Essential to developing these therapeutic strategies is to maintain physiologically low ROS levels in normal tissues while inducing ROS in cancer cells. GMX1778 is a specific inhibitor of nicotinamide phosphoribosyltransferase, a rate-limiting enzyme required for the regeneration of NAD(+) from nicotinamide. We show that GMX1778 increases intracellular ROS in cancer cells by elevating the superoxide level while decreasing the intracellular NAD(+) level. Notably, GMX1778 treatment does not induce ROS in normal cells. GMX1778-induced ROS can be diminished by adding nicotinic acid (NA) in a NA phosphoribosyltransferase 1 (NAPRT1)-dependent manner, but NAPRT1 is lost in a high frequency of glioblastomas, neuroblastomas, and sarcomas. In NAPRT1-deficient cancer cells, ROS induced by GMX1778 wa...Continue Reading

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Citations

Apr 27, 2013·Journal of Medicinal Chemistry·Xiaozhang ZhengKenneth W Bair
Jul 19, 2013·Journal of Medicinal Chemistry·Xiaozhang ZhengKenneth W Bair
Aug 16, 2013·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Jie SongChao-Yu Miao
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Aug 20, 2016·Journal of Medicinal Chemistry·Mark ZakPeter S Dragovich
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Jun 10, 2019·Seminars in Cell & Developmental Biology·Maheshwor Thapa, Guido Dallmann

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