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

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 antimetabolic strategies.

• Authors: Daniela Buonvicino, Francesca Mazzola, Federica Zamporlini, Francesco Resta, Giuseppe Ranieri, Emidio Camaioni, Mirko Muzzi, Riccardo Zecchi, Giuseppe Pieraccini, Christian Dölle, Massimo Calamante, Gianluca Bartolucci, Mathias Ziegler, Barbara Stecca, Nadia Raffaelli, Alberto Chiarugi
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 25 Issue 4 Pg. 471-482.e7 (04 19 2018) ISSN: 2451-9448 [Electronic] United States
• PMID: 29478906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Phenylurea Compounds
• NAD
• Niacinamide
• Nicotinamide Phosphoribosyltransferase
• pyriminil

Topics

• Animals
• Antimetabolites, Antineoplastic (metabolism, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Glycolysis (drug effects)
• Humans
• Melanoma (drug therapy, metabolism)
• Mice, Nude
• Models, Molecular
• NAD (metabolism)
• Neuroblastoma (drug therapy, metabolism)
• Niacinamide (metabolism)
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, metabolism)
• Phenylurea Compounds (metabolism, pharmacology, therapeutic use)