Identification of the nicotinamide salvage pathway as a new toxification route for antimetabolites
Open accessAbstract
Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD-dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2-positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetabolic strategies.
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Depleting cellular NAD+ and inhibiting NAD+ synthetic enzymes can trigger cancer cell death.
“strategies to deplete cellular NAD+ and the inhibition of NAD+ synthetic enzymes can trigger cancer cell death”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Buonvicino et al., 2018
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,260 · see citing works
Trott, O., & Olson, A. J. (2010) · Journal of Computational Chemistry · doi:10.1002/jcc.21334 · Cited by 38,412 · see citing works
LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery
Laskowski, R., & Swindells, M. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci200227u · Cited by 6,159 · see citing works
I-TASSER: a unified platform for automated protein structure and function prediction
Roy, A., Küçükural, A., & Zhang, Y. (2010) · Nature Protocols · doi:10.1038/nprot.2010.5 · Cited by 6,093 · see citing works
The I-TASSER Suite: protein structure and function prediction
Yang, J., Yan, R., Roy, A., Xu, D., Poisson, J., & Zhang, Y. (2015) · Nature Methods · doi:10.1038/nmeth.3213 · Cited by 5,596 · see citing works
Assessment of protein models with three-dimensional profiles
Lüthy, R., Bowie, J., & Eisenberg, D. (1992) · Nature · doi:10.1038/356083a0 · Cited by 3,588 · see citing works
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013 · see citing works
Enzyme kinetics; behavior and analysis of rapid equilibrium and steady state enzyme systems
(1994) · International Journal of Biochemistry · doi:10.1016/0020-711x(94)90021-3 · Cited by 2,978 · see citing works
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
Metabolic pathways promoting cancer cell survival and growth
Boroughs, L. K., & DeBerardinis, R. J. (2015) · Nature Cell Biology · doi:10.1038/ncb3124 · Cited by 1,459 · see citing works
Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S.-I. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.014 · Cited by 1,340 · see citing works
NAD <sup>+</sup> in aging, metabolism, and neurodegeneration
Verdin, E. (2015) · Science · doi:10.1126/science.aac4854 · Cited by 1,319 · see citing works
Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M. E., Apte, R. S., Uchida, K., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.013 · Cited by 930 · see citing works
Nampt/PBEF/Visfatin Regulates Insulin Secretion in β Cells as a Systemic NAD Biosynthetic Enzyme
Revollo, J. R., Körner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., Dasgupta, B., Sasaki, Y., Wolberger, C., Townsend, R. R., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.09.003 · Cited by 911 · see citing works
Bieganowski, P., & Brenner, C. (2004) · Cell · doi:10.1016/s0092-8674(04)00416-7 · Cited by 750 · see citing works
Pedretti, A., Villa, L., & Vistoli, G. (2004) · Journal of Computer-Aided Molecular Design · doi:10.1023/b:jcam.0000035186.90683.f2 · Cited by 729 · see citing works
Bogan, K. L., & Brenner, C. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155443 · Cited by 707 · see citing works
The NAD metabolome — a key determinant of cancer cell biology
Chiarugi, A., Dölle, C., Felici, R., & Ziegler, M. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3340 · Cited by 645 · see citing works
Self-citationWallerian degeneration: an emerging axon death pathway linking injury and disease
Conforti, L., Gilley, J., & Coleman, M. P. (2014) · Nature reviews. Neuroscience · doi:10.1038/nrn3680 · Cited by 611 · see citing works
Berger, F., Lau, C., Dahlmann, M., & Ziegler, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508660200 · Cited by 508 · see citing works
Self-citationPoly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited
Chiarugi, A. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)01902-7 · Cited by 298 · see citing works
Self-citationInhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer
Sampath, D., Zabka, T. S., Misner, D. L., O’Brien, T., & Dragovich, P. S. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.02.004 · Cited by 258 · see citing works
SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells
Santini, R., Pietrobono, S., Pandolfi, S., Montagnani, V., D’Amico, M., Penachioni, J. Y., Vinci, M. C., Borgognoni, L., & Stecca, B. A. (2014) · Oncogene · doi:10.1038/onc.2014.71 · Cited by 200 · see citing works
Self-citationInhibition of Nicotinamide Phosphoribosyltransferase
Pittelli, M., Formentini, L., Faraco, G., Lapucci, A., Rapizzi, E., Cialdai, F., Romano, G., Moneti, G., Moroni, F., & Chiarugi, A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.136739 · Cited by 189 · see citing works
Self-citationNAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice
Lin, J. B., Kubota, S., Ban, N., Yoshida, M., Santeford, A. C., Sène, A., Nakamura, R. E. I., Zapata, N., Kubota, M., Tsubota, K., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.073 · Cited by 185 · see citing works
Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues
Mori, V., Amici, A., Mazzola, F., Stefano, M. D., Conforti, L., Magni, G., Ruggieri, S., Raffaelli, N., & Orsomando, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113939 · Cited by 158 · see citing works
Self-citationMedicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors
Galli, U., Travelli, C., Massarotti, A., Fakhfouri, G., Rahimian, R., Tron, G. C., & Genazzani, A. A. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4001049 · Cited by 155 · see citing works
Nuclear Poly(ADP-ribose) Polymerase-1 Rapidly Triggers Mitochondrial Dysfunction
Cipriani, G., Rapizzi, E., Vannacci, A., Rizzuto, R., Moroni, F., & Chiarugi, A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414526200 · Cited by 148 · see citing works
Self-citationZhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., & Zhang, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300073200 · Cited by 136 · see citing works
Nicotinamide Phosphoribosyltransferase in Malignancy: A Review
Shackelford, R. E., Mayhall, K., Maxwell, N. M., Kandil, E. H., & Coppola, D. (2013) · Genes & Cancer · doi:10.1177/1947601913507576 · Cited by 127 · see citing works
Burgos, E. S., & Schramm, V. L. (2008) · Biochemistry · doi:10.1021/bi801198m · Cited by 123 · see citing works
Piacente, F., Caffa, I., Ravera, S., Sociali, G., Passalacqua, M., Vellone, V. G., Becherini, P., Reverberi, D., Monacelli, F., Ballestrero, A., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3079 · Cited by 113 · see citing works
Poly(ADP-ribose) Catabolism Triggers AMP-dependent Mitochondrial Energy Failure
Formentini, L., Macchiarulo, A., Cipriani, G., Camaioni, E., Rapizzi, E., Pellicciari, R., Moroni, F., & Chiarugi, A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.002931 · Cited by 90 · see citing works
Self-citationSorci, L., Cimadamore, F., Scotti, S., Petrelli, R., Cappellacci, L., Franchetti, P., Orsomando, G., & Magni, G. (2007) · Biochemistry · doi:10.1021/bi6023379 · Cited by 86 · see citing works
Structure of Human Nicotinamide/Nicotinic Acid Mononucleotide Adenylyltransferase
Zhou, T., Kurnasov, O. V., Tomchick, D. R., Binns, D. D., Grishin, N. V., Márquez, V. E., Osterman, A. L., & Zhang, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111469200 · Cited by 86 · see citing works
Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells
Kulikova, V., Shabalin, K., Nerinovski, K., Dölle, C., Niere, M., Yakimov, A., Redpath, P., Khodorkovskiy, M., Migaud, M. E., Ziegler, M., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.664458 · Cited by 84 · see citing works
Self-citationRecent development of IMP dehydrogenase inhibitors for the treatment of cancer.
Chen, L., & Pankiewicz, K. W. (2007) · PubMed · Cited by 82 · see citing works
Assay methods for nicotinamide mononucleotide adenylyltransferase of wide applicability.
Balducci, E., Emanuelli, M., Raffaelli, N., Ruggieri, S., Amici, A., Magni, G., Orsomando, G., Polzonetti, V., & Natalini, P. (1995) · Analytical Biochemistry · doi:10.1006/abio.1995.1315 · Cited by 79 · see citing works
Self-citationAntitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model
Sociali, G., Raffaghello, L., Magnone, M., Zamporlini, F., Emionite, L., Sturla, L., Bianchi, G., Vigliarolo, T., Nahimana, A., Nencioni, A., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6502 · Cited by 70 · see citing works
Self-citationPreclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777
Beauparlant, P., Bédard, D., Bernier, C., Chan, H. H. L., Gilbert, K., Goulet, D., Gratton, M., Lavoie, M., Roulston, A., Turcotte, É., et al. (2009) · Anti-Cancer Drugs · doi:10.1097/cad.0b013e3283287c20 · Cited by 67 · see citing works
The Neurotoxicity of the Rat Poison Vacor
LeWitt, P. A. (1980) · New England Journal of Medicine · doi:10.1056/nejm198001103020202 · Cited by 67 · see citing works
Yalowitz, J. A., Xiao, S., Biju, M. P., Antony, A. C., Cummings, O. W., Deeg, M. A., & Jayaram, H. N. (2004) · Biochemical Journal · doi:10.1042/bj20030518 · Cited by 58 · see citing works
Nicotinamide phosphoribosyltransferase ( NAMPT ) is over‐expressed in melanoma lesions
Maldi, E., Travelli, C., Caldarelli, A., Agazzone, N., Cintura, S., Galli, U., Scatolini, M., Ostano, P., Miglino, B., Chiorino, G., et al. (2012) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12037 · Cited by 54 · see citing works
New strategies to maximize therapeutic opportunities for NAMPT inhibitors in oncology
Roulston, A., & Shore, G. C. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1052180 · Cited by 54 · see citing works
Oh, A., Ho, Y., Zak, M., Liu, Y., Chen, X., Yuen, P., Zheng, X., Liu, Y., Dragovich, P. S., & Wang, W. (2014) · ChemBioChem · doi:10.1002/cbic.201402023 · Cited by 51 · see citing works
Zamporlini, F., Ruggieri, S., Mazzola, F., Amici, A., Orsomando, G., & Raffaelli, N. (2014) · FEBS Journal · doi:10.1111/febs.13050 · Cited by 48 · see citing works
Self-citationStructure and reaction mechanism of human nicotinamide phosphoribosyltransferase
Takahashi, R., Nakamura, S., Nakazawa, T., Minoura, K., Yoshida, T., Nishi, Y., Kobayashi, Y., & Ohkubo, T. (2009) · The Journal of Biochemistry · doi:10.1093/jb/mvp152 · Cited by 44 · see citing works
Brunetti, L., Stefano, M. D., Ruggieri, S., Cimadamore, F., & Magni, G. (2010) · Protein Science · doi:10.1002/pro.526 · Cited by 23 · see citing works
Poisoning with vacor rodenticide.
Rp, V. (1982) · PubMed · Cited by 1 · see citing works
Flagged first, then by citations
1 of the 50 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
Programmed axon degeneration: from mouse to mechanism to medicine
Coleman, M. P., & Höke, A. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0269-3 · Cited by 320 · see citing works
Ronchetti, R., Moroni, G., Carotti, A., Gioiello, A., & Camaioni, E. (2021) · RSC Medicinal Chemistry · doi:10.1039/d1md00058f · Cited by 241 · see citing works
Self-citationNAD Metabolism in Cancer Therapeutics
Yaku, K., Okabe, K., Hikosaka, K., & Nakagawa, T. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00622 · Cited by 229 · see citing works
Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy
Galli, U., Colombo, G., Travelli, C., Tron, G. C., Genazzani, A. A., & Grolla, A. A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00656 · Cited by 162 · see citing works
“The interplay between NAMPT inhibitors and NAPRT already has strong foundations (Buonvicino et al., 2018).”
BackgroundNeuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering
Tribble, J. R., Hui, F., Quintero, H., Hajji, S. E., Bell, K. C., Polo, A. D., & Williams, P. A. (2023) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2023.101193 · Cited by 115 · see citing works
Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy
Heske, C. M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01514 · Cited by 110 · see citing works
Angeletti, C., Amici, A., Gilley, J., Loreto, A., Trapanotto, A. G., Antoniou, C., Merlini, E., Coleman, M. P., & Orsomando, G. (2022) · iScience · doi:10.1016/j.isci.2022.103812 · Cited by 95 · see citing works
Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies
Zhu, Y., Liu, J., Park, J., Rai, P., & Zhai, R. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.04.002 · Cited by 82 · see citing works
“VAD rapidly depletes NAD+ pools, blocks glycolysis through inhibition of NAD +-dependent dehydrogenases, and significantly reduces the growth of NMNAT2-proficient neuroblastoma and melanoma xenografts (Buonvicino et al., 2018).”
BackgroundTryptophan metabolism and disposition in cancer biology and immunotherapy
Badawy, A. A. ‐. (2022) · Bioscience Reports · doi:10.1042/bsr20221682 · Cited by 75 · see citing works
Managò, A., Audrito, V., Mazzola, F., Sorci, L., Gaudino, F., Gizzi, K., Vitale, N., Incarnato, D., Minazzato, G., Ianniello, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12055-2 · Cited by 71 · see citing works
Self-citationNeurotoxin-mediated potent activation of the axon degeneration regulator SARM1
Loreto, A., Angeletti, C., Gu, W., Osborne, A., Nieuwenhuis, B., Gilley, J., Arthur‐Farraj, P., Merlini, E., Amici, A., Luo, Z., et al. (2021) · eLife · doi:10.7554/elife.72823 · Cited by 70 · see citing works
“Furthermore, NMN and NAD levels and their ratio to one another were not altered in our vacor- treated Sarm1 neurons (Figure 4A and B), suggesting that the reported inhibition of NAMPT and NMNAT2 by vacor/VAD (Buonvicino et al., 2018) does not occur in this context at this drug concentration.”
BackgroundMethodInfluentialAdvances in NAD-Lowering Agents for Cancer Treatment
Ghanem, M. S., Monacelli, F., & Nencioni, A. (2021) · Nutrients · doi:10.3390/nu13051665 · Cited by 69 · see citing works
“It was recently shown to have cytotoxic activity against NMNAT2-expressing cancer cells [126].”
BackgroundInfluentialSIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells
Sociali, G., Grozio, A., Caffa, I., Schuster, S., Becherini, P., Damonte, P., Sturla, L., Fresia, C., Passalacqua, M., Mazzola, F., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201800321r · Cited by 68 · see citing works
Self-citationIdentification of evolutionary and kinetic drivers of NAD-dependent signaling
Bockwoldt, M., Houry, D., Niere, M., Gossmann, T. I., Reinartz, I., Schug, A. H., Ziegler, M., & Heiland, I. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1902346116 · Cited by 67 · see citing works
“It has now become clear that inhibition of NAD biosynthesis leads to a rapid decline of the cellular NAD concentration (13, 31).”
BackgroundSelf-citationMetabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD
Taubenheim, J., Kadibalban, A. S., Zimmermann, J., Taubenheim, C., Tran, F., Schreiber, S., Rosenstiel, P. C., Aden, K., & Kaleta, C. (2025) · Nature Communications · doi:10.1038/s41467-025-60233-2 · Cited by 64 · see citing works
Aman, Y., Frank, J., Lautrup, S., Matysek, A., Niu, Z., Yang, G., Shi, L., Bergersen, L. H., Storm‐Mathisen, J., Rasmussen, L. J., et al. (2019) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2019.111194 · Cited by 60 · see citing works
“Thus, strategies to deplete cellular NAD + and the inhibition of NAD + synthetic enzymes can trigger cancer cell death (Buonvicino et al., 2018).”
BackgroundNAD+ Metabolism in Aging and Cancer
Demarest, T. G., Babbar, M., Okur, M. N., Dan, X., Croteau, D. L., Fakouri, N. B., Mattson, M. P., & Bohr, V. A. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055905 · Cited by 57 · see citing works
“While NAMPT has been considered the rate-limiting step of the NAD+ salvage pathway, it is important to note that NAD+ production from any of the biosynthetic pathways requires NMNATs as the terminal step for NAD+ synthesis (Buonvicino et al. 2018).”
BackgroundNeurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss
Wu, T., Zhu, J., Strickland, A. M., Ko, K. W., Sasaki, Y., Dingwall, C. B., Yamada, Y., Figley, M. D., Mao, X. R., Neiner, A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109872 · Cited by 45 · see citing works
NAD+ Metabolism and Immune Regulation: New Approaches to Inflammatory Bowel Disease Therapies
Chen, C., Yan, W., Tao, M., & Fu, Y. (2023) · Antioxidants · doi:10.3390/antiox12061230 · Cited by 44 · see citing works
Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives
Poltronieri, P., Celetti, A., & Palazzo, L. (2021) · Cells · doi:10.3390/cells10010128 · Cited by 39 · see citing works
Buonvicino, D., Urru, M., Muzzi, M., Ranieri, G., Luceri, C., Oteri, C., Lapucci, A., & Chiarugi, A. (2018) · Pain · doi:10.1097/j.pain.0000000000001291 · Cited by 37 · see citing works
Self-citationGrolla, A. A., Miggiano, R., Marino, D. D., Bianchi, M., Gori, A., Orsomando, G., Gaudino, F., Galli, U., Grosso, E. D., Mazzola, F., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010571 · Cited by 36 · see citing works
Self-citationTanamai, J., Veeramanomai, S., & Indrakosas, N. (2004) · PubMed · Cited by 35 · see citing works
Fortunato, C., Mazzola, F., & Raffaelli, N. (2021) · IUBMB Life · doi:10.1002/iub.2584 · Cited by 34 · see citing works
“Recently, a weak inhibition of NMNAT2 was found to be exerted by the NAD analog VAD.(91)”
BackgroundInfluentialSelf-citationGasparrini, M., Mazzola, F., Cuccioloni, M., Sorci, L., Audrito, V., Zamporlini, F., Fortunato, C., Amici, A., Cianci, M., Deaglio, S., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101669 · Cited by 30 · see citing works
“The plasmid pET15-b harboring the wildtype NAMPT gene (42) was used as a template for PCR mutagenic reactions.”
MethodInfluentialSelf-citationInhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives
Ghanem, M. S., Caffa, I., Monacelli, F., & Nencioni, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042092 · Cited by 28 · see citing works
Unified and green oxidation of amides and aldehydes for the Hofmann and Curtius rearrangements
Song, L., Meng, Y., Zhao, T., Liu, L., Pan, X., Huang, B., Yao, H., Lin, R., & Tong, R. (2023) · Green Chemistry · doi:10.1039/d3gc04355j · Cited by 27 · see citing works
Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death
Reddy, V. G., Krider, I. S., Alves, E. T. M., Courey, J. M., Laham, M. S., & Thatcher, G. R. J. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02112 · Cited by 27 · see citing works
Immunometabolism: A ‘Hot’ Switch for ‘Cold’ Pediatric Solid Tumors
Xiao, L., Yeung, H., Haber, M., Norris, M. D., & Somers, K. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.05.002 · Cited by 25 · see citing works
Enzymatic and Chemical Syntheses of Vacor Analogs of Nicotinamide Riboside, NMN and NAD
Sverkeli, L. J., Hayat, F., Migaud, M. E., & Ziegler, M. (2021) · Biomolecules · doi:10.3390/biom11071044 · Cited by 22 · see citing works
“Critically, current methods to produce vacor analogs of NAD and its biosynthetic intermediates are rather complex and time consuming, as they involve expression and purification of the enzymes of the salvage pathway of the NAD biosynthesis [20,22].”
BackgroundMethodInfluentialSelf-citationNMNAT2: An important metabolic enzyme affecting the disease progression
Li, W., Gao, M., Hu, C., Chen, X., & Zhou, Y. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114143 · Cited by 21 · see citing works
Kitada, M., Araki, S., & Koya, D. (2023) · Cells · doi:10.3390/cells12040595 · Cited by 21 · see citing works
Neurotoxin-mediated --potent activation of the axon degeneration regulator SARM1.
Loreto, A., Angeletti, C., Gu, W., Osborne, A., Nieuwenhuis, B., Gilley, J., Merlini, E., Arthur‐Farraj, P., Amici, A., Luo, Z., et al. (2021) · Apollo (University of Cambridge) · doi:10.17863/cam.79086 · Cited by 20 · see citing works
Buonvicino, D., Ranieri, G., Pratesi, S., Guasti, D., & Chiarugi, A. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113065 · Cited by 18 · see citing works
“Cell luminescence was evaluated after 5 min by means of a luminometer (Buonvicino et al., 2018).”
MethodSelf-citationSIRT1-dependent restoration of NAD+ homeostasis after increased extracellular NAD+ exposure
Buonvicino, D., Ranieri, G., Pittelli, M. G., Lapucci, A., Bragliola, S., & Chiarugi, A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100855 · Cited by 17 · see citing works
“Quantitation of oxygen consumption was conducted by means of the Oxygraph system (Hansatech Instruments) as reported (70).”
MethodSelf-citationTargeting metabolic dependencies in pediatric cancer
Issaq, S. H., & Heske, C. M. (2019) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000853 · Cited by 15 · see citing works
Buonvicino, D., Ranieri, G., Pratesi, S., Gerace, E., Muzzi, M., Guasti, D., Tofani, L., & Chiarugi, A. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15058 · Cited by 15 · see citing works
“RT-PCR was performed as reported (Buonvicino et al., 2018).”
MethodSelf-citationUrru, M., Buonvicino, D., Pistolesi, A., Paccosi, S., & Chiarugi, A. (2022) · Journal of Pain · doi:10.1016/j.jpain.2022.05.007 · Cited by 14 · see citing works
Self-citationLoreto, A., Cramb, K. M. L., McDermott, L., Antoniou, C., Cirilli, I., Caiazza, M. C., Merlini, E., Arthur‐Farraj, P., du Preez, W. D., Mock, E. D., et al. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106986 · Cited by 14 · see citing works
“Both SARM1 and NMNAT2 play a pivotal role in nicotinamide adenine dinucleotide (NAD) metabolism.”
InfluentialDexpramipexole enhances hippocampal synaptic plasticity and memory in the rat
Coppi, E., Lana, D., Cherchi, F., Fusco, I., Buonvicino, D., Urru, M., Ranieri, G., Muzzi, M., Iovino, L., Giovannini, M. G., et al. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.10.003 · Cited by 14 · see citing works
Self-citationMcKay-Corkum, G. B., Collins, V. J., Yeung, C. L., Ito, T., Issaq, S. H., Holland, D. O., Vulikh, K., Zhang, Y., Lee, U., Lei, H., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0200 · Cited by 15 · see citing works
SARM1 is responsible for calpain-dependent dendrite degeneration in mouse hippocampal neurons
Miyamoto, T., Kim, C., Chow, J., Dugas, J. C., DeGroot, J., Bagdasarian, A. L., Thottumkara, A. P., Larhammar, M., Calvert, M., Fox, B. M., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.105630 · Cited by 13 · see citing works
“While CZ-48 is an NMN analog, Vacor requires processing by nicotinamide phosphoribosyltransferase (NAMPT) to produce the NMN analog VMN, which directly activates SARM1 (20, 23, 32).”
BackgroundZhu, X., Li, Y., Liu, H., Wang, Y., Sun, R., Jiang, Z., Hou, C., Hou, X., Huang, S., Zhang, H., et al. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.05.007 · Cited by 13 · see citing works
NAMPT Inhibition Induces Neuroblastoma Cell Death and Blocks Tumor Growth
Vallejo, F. A., Sanchez, A., Cuglievan, B., Walters, W. M., Angulo, G. D., Vanni, S., & Graham, R. M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.883318 · Cited by 10 · see citing works
“One study demonstrated slower NB progression when treated with daily 20mg/Kg Vacor, an NMNAT2 inhibitor previously used as a rodenticide, when compared with control mice (43).”
MethodHaubrich, B. A., Ramesha, C. S., & Swinney, D. C. (2019) · SLAS DISCOVERY · doi:10.1177/2472555219879644 · Cited by 10 · see citing works
“Most recently, a ureyl NMN analog, Vacor adenine dinucleotide, was found to have IC50 values for NMNAT2 and NMNAT3 of 20 and 463 μM, respectively, with no detectible effect on NMNAT1 activity.(30) Not surprisingly, our screen of the NCI mechanistic set, which contains several adenosine analogs and other ATP-competitiv…”
BackgroundColombo, G., Gelardi, E. L. M., Balestrero, F. C., Moro, M., Travelli, C., & Genazzani, A. A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.758320 · Cited by 9 · see citing works
“Yet, at present no potent NMNAT inhibitor has been developed (Petrelli et al., 2011; Buonvicino et al., 2018), with the exception of 2,3-dibromo-1,4naphthoquinone (Haubrich et al., 2020), which nonetheless lacks selectivity against the different isoforms and possibly acts also on other targets.”
BackgroundSilveira, S. C., Buhagiar‐Labarchède, G., Onclercq, R., Gemble, S., Samra, E. B., Mameri, H., Duchambon, P., Machon, C., Guitton, J., & Amor-Guéret, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-70874-6 · Cited by 9 · see citing works
A T-cell antigen atlas for meningioma: novel options for immunotherapy
Medici, G., Freudenmann, L. K., Velz, J., Wang, S., Kapolou, K., Paramasivam, N., Mühlenbruch, L., Kowalewski, D. J., Vasella, F., Bilich, T., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02605-w · Cited by 8 · see citing works
“NMNA2 is known to promote cancer cell survival, whereas WNT5A is a member of the oncogenic WNT protein family and is expressed in meningioma and many other tumors [6, 7, 17, 18, 33, 42].”
BackgroundTargeting SARM1: from inhibition for neuroprotection to activation for neuroablation
Arthur‐Farraj, P., & Loreto, A. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.09.003 · Cited by 7 · see citing works
3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes
Gencarelli, M., Laurino, A., Landucci, E., Buonvicino, D., Mazzantini, C., Chiellini, G., & Raimondi, L. (2020) · Biology · doi:10.3390/biology9050095 · Cited by 7 · see citing works
“Evaluation of ATP Cell Levels Cellular ATP content was measured by means of an ATP luminescence system (Perkin Elmer, Milan, Italy) [23].”
MethodSelf-citationWu, H., Meng, Q., Zhang, Y., Li, H., Liu, Y. U., Dong, S., Liu, B., & Zhang, H. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.11.019 · Cited by 6 · see citing works
Paoletti, N., Giovannuzzi, S., Gasparrini, M., Ammara, A., Zaroon, Z., Raffaelli, N., de Nigris, F., Gratteri, P., Supuran, C. T., & Nocentini, A. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c03157 · Cited by 5 · see citing works
Self-citationSmall Molecule Regulators Targeting NAD+ Biosynthetic Enzymes
Cen, Y., Curry, A. M., & White, D. S. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210531144629 · Cited by 5 · see citing works
The rise and fall of SARM1 base-exchange inhibitors
Lundbäck, T., Chandrasekar, V., Gu, C., Ju, H., McAdam, R. L., Palomero, M., Sader, K., Peter, B., Wissler, L., Nevin, P., et al. (2026) · Communications Chemistry · doi:10.1038/s42004-026-02074-8 · Cited by 4 · see citing works
Brüll, M., Multrus, S., Schäfer, M., Celardo, I., Karreman, C., & Leist, M. (2025) · Cell Death and Disease · doi:10.1038/s41419-024-07326-w · Cited by 3 · see citing works
Alminderej, F. M., & Aroua, L. M. (2026) · ChemistrySelect · doi:10.1002/slct.202504328 · Cited by 2 · see citing works
Recent Advances in Drug Development Targeting Cancer Metabolism
Sugandha, N., Mittal, L., Awasthi, A., & Asthana, S. (2020) · Springer eBooks · doi:10.1007/978-981-15-1991-8_8 · Cited by 2 · see citing works
Theodoropoulos, P. C., Guo, H. H., Wang, W., Crossley, E., Rivera‐Cancel, G., Fang, M., Nguyen, T. H., Baniasadi, H. R., Williams, N. S., Ready, J. M., et al. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00170 · Cited by 1 · see citing works
Cancer cell death induced by the NAD antimetabolite Vacor discloses the antitumor potential of SARM1
Ranieri, G., Lapucci, A., Orsomando, G., Raffaelli, N., Chiarugi, A., & Buonvicino, D. (2025) · FEBS Letters · doi:10.1002/1873-3468.70169 · Cited by 1 · see citing works
Self-citationThe Roles of Moonlighting Nicotinamide Mononucleotide Adenylyl Transferases in Cell Physiology
Lee, Y., & Lin, S.-J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26189098 · Cited by 2 · see citing works
“However, NAMPT inhibitors deplete NAD + slowly (24–48 h) [164,165], whereas VAD treatment is shown to nearly deplete NAD + in 3 h in vitro [164].”
Li, M., Li, X., Zheng, Y., Wang, Z., & Shi, L. (2025) · Frontiers in Zoology · doi:10.1186/s12983-025-00582-2 · Cited by 2 · see citing works
Matteucci, F., Ferrati, M., Spinozzi, E., Piergentili, A., Bello, F. D., Giorgioni, G., Sorci, L., Petrelli, R., & Cappellacci, L. (2024) · Pharmaceuticals · doi:10.3390/ph17060739 · Cited by 1 · see citing works
“…h NMNAT-2 is the isoform involved in the activation of Vacor, an old rat poison that has shown toxicity to h NMNAT-2-expressing cancer cells [14]. h NMNAT-2 is also highly expressed in a variety of solid tumors like colorectal, lung, and ovarian cancers, where it plays a significant role in…”
BackgroundAxon Degeneration: Which Method to Choose?
Coleman, M. P. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0585-1_1 · Cited by 1 · see citing works
Arrigoni, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.20.472904
“clear how to select a suitable target: the intrinsic collaborative fashion through which genes and proteins interact may lead to the emergence of ’salvage routes’[3], which render the modulation of a single component ineffective.”
BackgroundWeber, L. P. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-824315-2.00419-x
Huang, Z., Lin, S., Liang, Y., Khan, M., Chen, W., Li, X., Liu, X., Wu, Y. C., & Ye, J. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1852654
“NMNAT enzymes, particularly NMNAT2, play a critical role in regulating NAD synthesis, as multiple NAD biosynthesis pathways converge at this step (Buonvicino et al., 2018).”
Wang, K., Liu, Y., Zhang, Z., Hu, Y., Zhong, Y., Jiang, S., Zhang, X., Zhang, K., & Wang, T. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00353
SARM1-dependent antimetabolic cancer therapy
Molli, A., Buonvicino, D., Lapucci, A., Maresca, L., Lanza-Arnaiz, J. M., Polvani, S., Cialdai, F., Insero, G., Mello, T., Stecca, B. A., et al. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218762
Self-citationRecent Progress in Urea‐Containing Compounds as Tyrosine Kinase Inhibitors
Sroor, F. M. (2026) · Chemistry & Biodiversity · doi:10.1002/cbdv.71562
May, M., Fabela, R. F., & Tomanek, L. (2026) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2026.1914093
BindingDB (2025) · UC San Diego · doi:10.7270/q25x2fk7
The NAMPT–MMP-9 Axis Contributes to Chronic Inflammation in Cystic Fibrosis
Lori, L., Fiorilla, I., Ghezzi, B., Pedrazzi, M., Todesco, A. M., Mazzola, F., TULLIO, R. D., Cresta, F., Castellani, C., Patrone, M., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27219496
Self-citation
- Authors
- Buonvicino, D., Mazzola, F., Zamporlini, F., Resta, F., Ranieri, G., Camaioni, E., Muzzi, M., Zecchi, R., Pieraccini, G., Dölle, C., Calamante, M., Bartolucci, G., Ziegler, M., Stecca, B., Raffaelli, N., & Chiarugi, A.
- Affiliations
- University of Florence (IT)
- Marche Polytechnic University (IT)
- University of Perugia (IT)
- University of Bergen (NO)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- Corresponding author
- Chiarugi, Alberto
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 25
- Issue
- 4
- Pages
- 471-482.e7
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W2788251589
- Cited by
- 73
- References
- 50
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 13 · 2020: 10 · 2019: 8 · 2018: 5
- FWCI
- 4.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Funders
- Italian Foundation (2014/R/6)
- Regione Toscana Rare Disease Projects
- Ente Cassa di Risparmio di Firenze (ECRF 2015.0964)
- Ministry of Health (GR-2011-02352225)
- Associazione Italiana per la Ricerca sul Cancro (AIRC IG-2017-20451)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- nicotinamide salvage pathway, NAD+ metabolism, visfatin, NMNAT2, Vacor, antimetabolites, NAD+ depletion, NAD-dependent dehydrogenase, energy failure, necrosis, tumor cell growth inhibition, neuroblastoma, melanoma, drug resistance
- MeSH terms
- Animals, Antimetabolites, Antineoplastic, Cell Survival, Glycolysis, Humans, Melanoma, Mice, Nude, Models, Molecular, NAD, Neuroblastoma, Niacinamide, Phenylurea Compounds, Cell Line, Tumor, Nicotinamide Phosphoribosyltransferase
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