Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites

Cell Chemical Biology
Daniela BuonvicinoAlberto Chiarugi

Abstract

Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD-dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2-positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetaboli...Continue Reading

Citations

Dec 6, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Giovanna SocialiSantina Bruzzone
Dec 4, 2019·Current Opinion in Pediatrics·Sameer H Issaq, Christine M Heske
Mar 22, 2020·British Journal of Pharmacology·Daniela BuonvicinoAlberto Chiarugi
Jan 12, 2019·Frontiers in Oncology·Keisuke YakuTakashi Nakagawa
Jul 26, 2019·Proceedings of the National Academy of Sciences of the United States of America·Mathias BockwoldtInes Heiland
Mar 11, 2020·Nature Reviews. Neuroscience·Michael P Coleman, Ahmet Höke
Jun 2, 2020·Frontiers in Pharmacology·Ubaldina GalliAmbra A Grolla
Jun 3, 2021·Nutrients·Moustafa S GhanemAlessio Nencioni
Jun 8, 2021·The Journal of Biological Chemistry·Daniela BuonvicinoAlberto Chiarugi
Jun 30, 2021·Trends in Cancer·Lin XiaoKlaartje Somers
Aug 7, 2021·Biomolecules·Lars Jansen SverkeliMathias Ziegler

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