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.
NAD is a vital molecule in all organisms. It is a key component of both energy and signal transduction — processes that undergo crucial changes in cancer cells. NAD+-dependent signalling pathways are many and varied, and they regulate fundamental events such as transcription, DNA repair, cell cycle progression, apoptosis and metabolism. Many of these processes have been linked to cancer development. Given that NAD+-dependent signalling reactions involve the degradation of the molecule, permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. This necessity supports the targeting of NAD metabolism as a new therapeutic concept for cancer treatment.
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A.C. and R.F. would like to thank the Italian Foundation for Mutiple Sclerosis Research (FISM; grant 2009/R6) and Regione Toscana Progetto Salute 2009 for research funding. C.D. and M.Z. gratefully acknowledge financial support from the Norwegian Cancer Society (Kreftforeningen) and the Norwegian Research Council.
The authors declare no competing financial interests.
The reduced form of NAD.
The oxidated form of NAD.
A term used to indicate both oxidated and reduced forms of NAD.
Nicotinamide phosphoribosyltransferase. Also known as Visfatin and Pre-B cell colony-enhancing factor (PBEF). The abbreviation NamPRT is in keeping with the abbreviations of corresponding enzymes in nucleotide synthesis.
- Synthetic lethality
Two genes are synthetic lethal if mutation of either alone is compatible with viability but the mutation of both leads to death. Therefore, targeting a gene that is synthetic lethal to a cancer-relevant mutation should kill only cancer cells and should spare normal cells.
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Chiarugi, A., Dölle, C., Felici, R. et al. The NAD metabolome — a key determinant of cancer cell biology. Nat Rev Cancer 12, 741–752 (2012). https://doi.org/10.1038/nrc3340