The NAD metabolome — a key determinant of cancer cell biology

NAD is an important redox factor and substrate in various signalling processes, in which it is irreversibly degraded to form molecules that are of key relevance to cellular homeostasis. Both NAD+-dependent metabolic and signalling pathways are altered in cancer cells, providing a number of potential drug targets.Permanent synthesis of NAD is essential to fuel bioenergetic processes and maintain balanced cell regulation. NAD+ is synthesized from vitamin B3 (niacin, including both nicotinamide and nicotinic acid) and the corresponding nucleosides. However, the predominant source to maintain NAD levels is nicotinamide (Nam), which arises endogenously from NAD+-dependent signalling processes. Therefore, nicotinamide phosphoribosyltransferase (NamPRT) is of outstanding importance, as it is the only human enzyme that salvages Nam into NAD+ synthesis. NamPRT inhibitors are currently under scrutiny to evaluate their potential in cancer therapy based on NAD+ depletion.Likewise, inhibitors of nicotinamide mononucleotide adenylyltransferases (NMNATs) have the potential to affect NAD levels, as these enzymes are required in all pathways of NAD+ generation. Moreover, the expression of the three human isoforms is tissue- and cell compartment-specific, suggesting the possibility of more specific therapeutic approaches. However, so far, specific and potent inhibitors are not available.Several NAD-dependent signalling pathways are involved in the control of cell cycle progression, transcriptional regulation and DNA repair and have therefore been identified as promising targets in cancer therapy. The NAD+-dependent protein deacetylases (Sirtuins) SIRT1, SIRT3, SIRT6 and SIRT7 are also now of interest in the development of new cancer therapies.Inhibitors of polyADP ribose polymerases (PARPs) have a demonstrated potential in cancer therapy and have recently reached the clinical arena. Major current challenges in their use are selectivity towards specific PARP isoforms, potential impairment of DNA repair in healthy tissues and development of drug resistance.