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Review
. 2024 Feb 8;25(4):2092.
doi: 10.3390/ijms25042092.

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Moustafa S Ghanem  1 , Irene Caffa  1   2 , Fiammetta Monacelli  1   2 , Alessio Nencioni  1   2
Affiliations
Review

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Moustafa S Ghanem et al. Int J Mol Sci. .

Abstract

The addiction of tumors to elevated nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of cancer metabolism. Obstructing NAD+ biosynthesis in tumors is a new and promising antineoplastic strategy. Inhibitors developed against nicotinamide phosphoribosyltransferase (NAMPT), the main enzyme in NAD+ production from nicotinamide, elicited robust anticancer activity in preclinical models but not in patients, implying that other NAD+-biosynthetic pathways are also active in tumors and provide sufficient NAD+ amounts despite NAMPT obstruction. Recent studies show that NAD+ biosynthesis through the so-called "Preiss-Handler (PH) pathway", which utilizes nicotinate as a precursor, actively operates in many tumors and accounts for tumor resistance to NAMPT inhibitors. The PH pathway consists of three sequential enzymatic steps that are catalyzed by nicotinate phosphoribosyltransferase (NAPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), and NAD+ synthetase (NADSYN1). Here, we focus on these enzymes as emerging targets in cancer drug discovery, summarizing their reported inhibitors and describing their current or potential exploitation as anticancer agents. Finally, we also focus on additional NAD+-producing enzymes acting in alternative NAD+-producing routes that could also be relevant in tumors and thus become viable targets for drug discovery.

Keywords: NAD+; NADSYN; NAMPT; NAPRT; NMNAT; Preiss-Handler pathway; cancer metabolism; inhibitors.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Overview of NAD+-biosynthetic routes. Green arrows represent the pathways that could be enabled in response to the inhibition of the predominant salvage pathway (red arrow) by NAMPT inhibitors. The yellow arrow represents NAD+ consumption through diverse NAD+-degrading enzymes. This figure was created with BioRender.com (accessed on 28 January 2024).
Figure 2
Figure 2
Historic overview of the milestone discoveries regarding NAPRT and its inhibitors and their exploitation in cancer. The figure was created with BioRender.com (accessed on 28 January 2024).
Figure 3
Figure 3
NADSYN1 and human cancers. NADSYN1 gene mutations, deletions, amplifications, and multiple alterations in human cancer as demonstrated by the cBioPortal for Cancer Genomics (http://www.cbioportal.org/ accessed on 26 January 2024). The search engine was adjusted to show studies from the TCGA PanCancer Atlas with at least 3% of NADSYN1 alteration frequency. The “+” sign shows that samples were profiled for structural variants, mutations, and copy number alterations (CNA).
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