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Pharmacol Res. 2016 Dec;114:274-283. doi: 10.1016/j.phrs.2016.10.027. Epub 2016 Nov 2.

NAD+ salvage pathway in cancer metabolism and therapy.

Author information

1
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
2
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
3
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada.
4
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada; Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, NS, Canada. Electronic address: shashi.gujar@dal.ca.

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, cell growth, and cell death. Many of these pathways are typically dysregulated in cancer cells, making NAD+ an intriguing target for cancer therapeutics. NAD+ is mainly synthesized by the NAD+ salvage pathway in cancer cells, and not surprisingly, the pharmacological targeting of the NAD+ salvage pathway causes cancer cell cytotoxicity in vitro and in vivo. Several studies have described the precise consequences of NAD+ depletion on cancer biology, and have demonstrated that NAD+ depletion results in depletion of energy levels through lowered rates of glycolysis, reduced citric acid cycle activity, and decreased oxidative phosphorylation. Additionally, depletion of NAD+ causes sensitization of cancer cells to oxidative damage by disruption of the anti-oxidant defense system, decreased cell proliferation, and initiation of cell death through manipulation of cell signaling pathways (e.g., SIRT1 and p53). Recently, studies have explored the effect of well-known cancer therapeutics in combination with pharmacological depletion of NAD+ levels, and found in many cases a synergistic effect on cancer cell cytotoxicity. In this context, we will discuss the effects of NAD+ salvage pathway inhibition on cancer cell biology and provide insight on this pathway as a novel anti-cancer therapeutic target.

KEYWORDS:

Cancer; Energy metabolism; Nicotinamide adenine dinucleotide; Nicotinamide phosphoribosyltransferase

PMID:
27816507
DOI:
10.1016/j.phrs.2016.10.027
[Indexed for MEDLINE]

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