Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer

Abstract

NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation–reduction (redox) reactions in various energy production processes, such as the Krebs cycle, fatty acid oxidation, glycolysis and serine biosynthesis. Furthermore, high NAD+ levels are required since they also participate in many other nonredox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis. In these nonredox reactions, NAD+ is an ADP-ribose donor for enzymes such as sirtuins (SIRTs), poly-(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADPRs). Therefore, to meet both redox and nonredox NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. NAMPT, the rate-limiting enzyme of this pathway, has been identified as an oncogene in some cancer types. Thus, NAMPT has been proposed as a suitable target for cancer therapy. NAMPT inhibition causes the depletion of NAD+ content in the cell, leading to the inhibition of ATP synthesis. This effect can cause a decrease in tumour cell proliferation and cell death, mainly by apoptosis. Therefore, in recent years, many specific inhibitors of NAMPT have been developed, and some of them are currently in clinical trials. Here we review the NAD metabolism as a cancer therapy target.

Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice

“…To preliminarily elucidate the role of NAMPT in lung fibrosis, we used FK866, an enzymatic inhibitor of NAMPT 38 . Mice were injected intraperitoneally with various doses of FK866 (1, 3, 10 mg/kg) or an equal volume of the vehicle once a day, starting the day before modeling with bleomycin (3 mg/kg), and the mice were sacrificed for sample collection on day 14 after modeling (Figure 2 A).…”

Use of ultra-high performance liquid chromatography-high-resolution mass spectroscopy to profile the metabolites from the serum of patients with breast cancer

“…In the present study, pathway enrichment analysis revealed that the BC metabolic signaling pathways were also involved in nicotinic acid, nicotinamide, caffeine and purine metabolic pathways. Nicotinic acid and nicotinamide metabolism are associated with high turnover rates of nicotinamide adenine dinucleotide (NAD + ) in cancer cells, reflecting their high proliferation rates and DNA synthesis ( 34 ). Altered purine and uric acid metabolism may be due to increased tumor demand for substrates for nucleic acid biosynthesis ( 35 ).…”

Plasma-activated medium exerts tumor-specific inhib-itory effect on hepatocellular carcinoma via disruption of the salvage pathway

“…In previous studies on HCC and several other types of tumors, the down-regulation of NAMPT by either expression interference or inhibitory agents, could fundamentally interrupt the generation of intracellular NAD + and result in a dysfunction of glycolysis and a depletion of ATP (17) . Such a failure in energy metabolism halts a range of essential physiological events to cause cell death (18,19) , and up-regulation of AMP-activated protein kinase (AMPK) has been unraveled as one of the most outstanding downstream events (20) .…”