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Cell Chem Biol. 2018 Apr 19;25(4):471-482.e7. doi: 10.1016/j.chembiol.2018.01.012. Epub 2018 Feb 22.

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

Author information

1
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
2
Department of Clinical Science, Polytechnic University of Marche, Ancona 60131, Italy.
3
Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona 60131, Italy.
4
Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence 50139, Italy.
5
Department of Pharmaceutical Sciences, University of Perugia, Perugia 06123, Italy.
6
Mass Spectrometry Service Centre (CISM), University of Florence, Florence 50139, Italy.
7
Department of Molecular Biology, University of Bergen, 5020 Bergen, Norway.
8
Department of Chemistry, University of Florence, Florence 50019, Italy.
9
Core Research Laboratory-Istituto Toscano Tumori, Department of Oncology, Careggi University Hospital, Florence 50139, Italy.
10
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy. Electronic address: alberto.chiarugi@unifi.it.

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.

KEYWORDS:

NAD; NAMPT; NMNAT2; Vacor; dehydrogenases; glycolysis; melanoma cells; neuroblastoma cells; xenograft

PMID:
29478906
DOI:
10.1016/j.chembiol.2018.01.012
[Indexed for MEDLINE]
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