The NAD metabolome - A key determinant of cancer cell biology

Nature Reviews Cancer

Volumn 12, Issue 11, 2012, Pages 741-752

  Chiarugi, Alberto ^a   Dölle, Christian ^a   Felici, Roberta ^a   Ziegler, Mathias ^b  

^a UNIVERSITY OF FLORENCE   (Italy)

^b UNIVERSITY OF BERGEN   (Norway)

Author keywords

[No Author keywords available]

Indexed keywords

CD38 ANTIGEN; NICOTINAMIDE ADENINE DINUCLEOTIDE; SIRTUIN 1; SIRTUIN 2; SIRTUIN 3; SIRTUIN 6; SIRTUIN 7;

ADENOSINE DIPHOSPHATE RIBOSYLATION; APOPTOSIS; BIOSYNTHESIS; CANCER CELL; CELL CYCLE PROGRESSION; CELL PROLIFERATION; CYTOLOGY; DISEASE COURSE; DNA REPAIR; ENERGY; GENETIC TRANSCRIPTION; HUMAN; METABOLOME; METABOLOMICS; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

HUMANS; METABOLOME; NAD; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84867877340     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3340     Document Type: Review

References (134)

1. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85-95 (2011).
2. Hamanaka, R. B. & Chandel, N. S. Cell biology. Warburg effect and redox balance. Science 334, 1219-1220 (2011).
3. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033 (2009).
4. Berger, F., Ramirez-Hernandez, M. H. & Ziegler, M. The new life of a centenarian: signalling functions of NAD(P). Trends Biochem. Sci. 29, 111-118 (2004).
5. Houtkooper, R. H., Canto, C., Wanders, R. J. & Auwerx, J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 31, 194-223 (2010).
6. Bieganowski, P. & Brenner, C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 117, 495-502 (2004).
7. Berger, F., Lau, C., Dahlmann, M. & Ziegler, M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J. Biol. Chem. 280, 36334-36341 (2005).
8. Lau, C., Niere, M. & Ziegler, M. The NMN/NaMN adenylyltransferase (NMNAT) protein family. Front. Biosci. 14, 410-431 (2009).
9. Preiss, J. & Handler, P. Biosynthesis of diphosphopyridine nucleotide.1. Identification of intermediates. J. Biol. Chem. 233, 488-492 (1958).
10. Preiss, J. & Handler, P. Biosynthesis of diphosphopyridine nucleotide.2. Enzymatic aspects. J. Biol. Chem. 233, 493-500 (1958).
11. Magni, G., Orsomando, G., Raffelli, N. & Ruggieri, S. Enzymology of mammalian NAD metabolism in health and disease. Front. Biosci. 13, 6135-6154 (2008).
12. Balo-Banga, J. M. & Weber, G. Increased 5 phospho-? D ribose-1 diphosphate synthetase (ribosephosphate pyrophosphokinase, EC 2.7.6.1) activity in rat hepatomas. Cancer Res. 44, 5004-5009 (1984).
13. van Berg, A. A. et al. The IMP dehydrogenase inhibitor mycophenolic acid antagonizes the CTP synthetase inhibitor 3 deazauridine in MOLT 3 human leukemia cells: a central role for phosphoribosyl pyrophosphate. Biochem. Pharmacol. 50, 1095-1098 (1995).
14. Gossmann, T. I. et al. NAD+ biosynthesis and salvage-a phylogenetic perspective. FEBS J. 279, 3355-3363 (2012).
15. Burkle, A. Poly(ADP-ribose). The most elaborate metabolite of NAD+. FEBS J. 272, 4576-4589 (2005).
16. Hassa, P. O. & Hottiger, M. O. The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front. Biosci. 13, 3046-3082 (2008).
17. Schreiber, V., Dantzer, F., Ame, J. C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517-528 (2006).
18. Rechsteiner, M., Hillyard, D. & Olivera, B. M. Magnitude and significance of NAD turnover in human cell line D98/AH2. Nature 259, 695-696 (1976).
19. Revollo, J. R., Grimm, A. A. & Imai, S. I. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754-50763 (2004).
20. Rongvaux, A. et al. Pre B cell colony-enhancing factor, whose expression is up regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur. J. Immunol. 32, 3225-3234 (2002).
21. Samal, B. et al. Cloning and characterization of the cDNA encoding a novel human pre b cell colony-enhancing factor. Mol. Cell. Biol. 14, 1431-1437 (1994).
22. Garten, A., Petzold, S., Korner, A., Imai, S. & Kiess, W. Nampt: linking NAD biology, metabolism and cancer. Trends Endocrinol. Metab. 20, 130-138 (2009).
23. Hara, N., Yamada, K., Shibata, T., Osago, H. & Tsuchiya, M. Nicotinamide phosphoribosyltransferase/ visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS ONE. 6, e22781 (2011).
24. Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK SIRT1. Science 324, 654-657 (2009).
25. Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651-654 (2009).
26. Honjo, T., Nishizuka, Y., Hayaishi, O. & Kato, I. Diphtheria toxin-dependent adenosine diphosphate ribosylation of aminoacyl transferase 2 and inhibition of protein synthesis. J. Biol. Chem. 243, 3553-3555 (1968).
27. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795-800 (2000).
28. Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807-5811 (2000).
29. Smith, J. S. et al. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc. Natl Acad. Sci. USA 97, 6658-6663 (2000).
30. Jackson, M. D. & Denu, J. M. Structural identification of 2? and 3? O acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of ?-NAD+-dependent histone/protein deacetylases. J. Biol. Chem. 277, 18535-18544 (2002).
31. Tong, L. & Denu, J. M. Function and metabolism of sirtuin metabolite O acetyl-ADP-ribose. Biochim. Biophys. Acta 1804, 1617-1625 (2010).
32. Meszaros, L. G., Bak, J. & Chu, A. Cyclic ADP-ribose as an. endogenous regulator of the nonskeletal type ryanodine receptor Ca2+ channel. Nature 364, 76-79 (1993).
33. Lee, H. C. Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling. J. Biol. Chem. 280, 33693-33696 (2005).
34. Young, G. S., Choleris, E., Lund, F. E. & Kirkland, J. B. Decreased cADPR and increased NAD+ in the Cd38?/? mouse. Biochem. Biophys. Res. Commun. 346, 188-192 (2006).
35. Malavasi, F. et al. CD38 and chronic lymphocytic leukemia: a decade later. Blood 118, 3470-3478 (2011).
36. Chini, E. N. CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr. Pharm. Des. 15, 57-63 (2009).
37. Stevenson, G. T. CD38 as a therapeutic target. Mol. Med. 12, 345-346 (2006).
38. Koch-Nolte, F., Kernstock, S., Mueller-Dieckmann, C., Weiss, M. S. & Haag, F. Mammalian ADP-ribosyltransferases and ADP-ribosylhydrolases. Front. Biosci. 13, 6716-6729 (2008).
39. Kato, J. et al. ADP-ribosylarginine hydrolase regulates cell proliferation and tumorigenesis. Cancer Res. 71, 5327-5335 (2011).
40. Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nature Rev. Cancer 10, 293-301 (2010).
41. Tong, W. M., Cortes, U. & Wang, Z. Q. Poly(ADP-ribose) polymerase: a guardian angel protecting the genome and suppressing tumorigenesis. Biochim. Biophys. Acta 1552, 27-37 (2001).
42. Kraus, W. L. Transcriptional control by PARP 1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr. Opin. Cell Biol. 20, 294-302 (2008).
43. Krishnakumar, R. & Kraus, W. L. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol. Cell 39, 8-24 (2010).
44. Alano, C. C. & Swanson, R. A. Players in the PARP 1 cell-death pathway: JNK1 joins the cast. Trends Biochem. Sci. 31, 309-311 (2006).
45. Calvert, H. & Azzariti, A. The clinical development of inhibitors of poly(ADP-ribose) polymerase. Ann. Oncol. 22, i53-i59 (2011).
46. Papeo, G. et al. Poly(ADP-ribose) polymerase inhibition in cancer therapy: are we close to maturity? Expert. Opin. Ther. Pat. 19, 1377-1400 (2009).
47. Mangerich, A. & Burkle, A. How to kill tumor cells with inhibitors of poly(ADP-ribosyl)ation. Int. J. Cancer 128, 251-265 (2011).
48. Chan, D. A. & Giaccia, A. J. Harnessing synthetic lethal interactions in anticancer drug discovery. Nature Rev. Drug Discov. 10, 351-364 (2011).
49. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 5, 689-698 (2005).
50. Helleday, T. The underlying mechanisms for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol. Oncol. 5, 387-393 (2011).
51. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123-134 (2009).
52. Fong, P. C. et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J. Clin. Oncol. 28, 2512-2519 (2010).
53. Yap, T. A., Sandhu, S. K., Carden, C. P. & de Bono, J. S. Poly(ADP-ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J. Clin. 61, 31-49 (2011).
54. Chiarugi, A. A snapshot of chemoresistance to PARP inhibitors. Trends Pharmacol. Sci. 33, 42-48 (2012).
55. Chalkiadaki, A. & Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nature Rev. Endocrinol. 8, 287-296 (2012).
56. Sauve, A. A., Wolberger, C., Schramm, V. L. & Boeke, J. D. The biochemistry of sirtuins. Annu. Rev. Biochem. 75, 435-465 (2006).
57. Schwer, B. & Verdin, E. Conserved metabolic regulatory functions of sirtuins. Cell Metab. 7, 104-112 (2008).
58. Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230-10235 (2006).
59. Canto, C. & Auwerx, J. Targeting sirtuin 1 to improve metabolism: all you need is NAD+? Pharmacol. Rev. 64, 166-187 (2012).
60. Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253-295 (2010).
61. Alhazzazi, T. Y., Kamarajan, P., Verdin, E. & Kapila, Y. L. SIRT3 and cancer: tumor promoter or suppressor? Biochim. Biophys. Acta 1816, 80-88 (2011).
62. Deng, C. X. SIRT1, is it a tumor promoter or tumor suppressor? Int. J. Biol. Sci. 5, 147-152 (2009).
63. Chen, J. et al. Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. Cancer Res. 71, 4138-4149 (2011).
64. Wang, B. et al. NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response. Oncogene 30, 907-921 (2011).
65. Kim, J. E., Chen, J. J. & Lou, Z. K. DBC1 is a negative regulator of SIRT1. Nature 451, 583-586 (2008).
66. Zhao, W. H. et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587-590 (2008).
67. Firestein, R. et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020 (2008).
68. Wang, R. H. et al. Interplay among BRCA1, SIRT1, and survivin during BRCA1 associated tumorigenesis. Mol. Cell 32, 11-20 (2008).
69. Herranz, D. & Serrano, M. SIRT1: recent lessons from mouse models. Nature Rev. Cancer 10, 819-823 (2010).
70. Wang, R. H. et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312-323 (2008).
71. Luo, J., Su, F., Chen, D., Shiloh, A. & Gu, W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408, 377-381 (2000).
72. Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149-159 (2001).
73. Tao, R. D. et al. Sirt3 mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 40, 893-904 (2010).
74. Sundaresan, N. R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758-2771 (2009).
75. Kim, H. S. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41-52 (2010).
76. Finley, L. W. S. et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1 ? destabilization. Cancer Cell 19, 416-428 (2011).
77. Bell, E. L., Emerling, B. M., Ricoult, S. J. H. & Guarente, L. SirT3 suppresses hypoxia inducible factor 1 ? and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30, 2986-2996 (2011).
78. Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095-1107 (2007).
79. Hiratsuka, M. et al. Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem. Biophys. Res. Commun. 309, 558-566 (2003).
80. Kim, H. S. et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20, 487-499 (2011).
81. Tennen, R. I. & Chua, K. F. Chromatin regulation and genome maintenance by mammalian SIRT6. Trends Biochem. Sci. 36, 39-46 (2011).
82. Mao, Z. Y. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443-1446 (2011).
83. Bai, P. et al. PARP 1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461-468 (2011).
84. Pillai, J. B., Isbatan, A., Imai, S. & Gupta, M. P. Poly(ADP-ribose) polymerase-1 dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2? deacetylase activity. J. Biol. Chem. 280, 43121-43130 (2005).
85. Zhang, J. Are poly(ADP-ribosyl)ation by PARP 1 and deacetylation by Sir2 linked? Bioessays 25, 808-814 (2003).
86. Van Meter, M., Mao, Z. Y., Gorbunova, V. & Seluanov, A. SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle 10, 3153-3158 (2011).
87. Ashraf, N. et al. Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer 95, 1056-1061 (2006).
88. de Nigris, F. et al. Isolation of a SIR-like gene, SIR T8, that is overexpressed in thyroid carcinoma cell lines and tissues. Br. J. Cancer 87, 1479 (2002).
89. Frye, R. 'SIRT8' expressed in thyroid cancer is actually SIRT7. Br. J. Cancer 87, 1479 (2002).
90. Barber, M. F. et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487, 114-118 (2012).
91. Huang, J. Y., Hirschey, M. D., Shimazu, T., Ho, L. & Verdin, E. Mitochondrial sirtuins. Biochim. Biophys. Acta 1804, 1645-1651 (2010).
92. Bogan, K. L. & Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28, 115-130 (2008).
93. Wu, C. et al. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 10, R130 (2009).
94. Belenky, P., Bogan, K. L. & Brenner, C. NAD+ metabolism in health and disease. Trends Biochem. Sci. 32, 12-19 (2007).
95. de Figueiredo, L. F., Gossmann, T. I., Ziegler, M. & Schuster, S. Pathway analysis of NAD+ metabolism. Biochem. J. 439, 341-348 (2011).
96. Zhang, L. Q., Heruth, D. P. & Ye, S. Q. Nicotinamide phosphoribosyltransferase in human diseases. J. Bioanal. Biomed. 3, 13-25 (2011).
97. Raffaelli, N. et al. Identification of a novel human nicotinamide mononucleotide adenylyltransferase. Biochem. Biophys. Res. Commun. 297, 835-840 (2002).
98. Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010).
99. Berger, F., Lau, C. & Ziegler, M. Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1. Proc. Natl Acad. Sci. 104, 3765-3760 (2007).
100. Zhang, T. et al. Regulation of poly(ADP-ribose) polymerase-1 dependent gene expression through promoter-directed recruitment of a nuclear NAD+ synthase. J. Biol. Chem. 287, 12405-12416 (2012).
101. Nikiforov, A., D?lle, C., Niere, M. & Ziegler, M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J. Biol. Chem. 286, 21767-21778 (2011).
102. Pittelli, M. et al. Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol. Pharmacol. 80, 1136-1146 (2011).
103. Stein, L. R. & Imai, S. I. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol. Metab., 23, 420-428 (2012).
104. Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555-1559 (2009).
105. Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278-1283 (2011).
106. Branster, M. V. & Morton, R. K. Comparative rates of synthesis of diphosphopyridine nucleotide by normal and tumour tissue from mouse mammary gland; studies with isolated nuclei. Biochem. J. 63, 640-646 (1956).
107. Morton, R. K. Enzymic synthesis of coenzyme I in relation to chemical control of cell growth. Nature 181, 540-542 (1958).
108. Petrelli, R., Felczak, K. & Cappellacci, L. NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK) inhibitors: chemistry and potential therapeutic applications. Curr. Med. Chem. 18, 1973-1992 (2011).
109. Jayaram, H. N. Biochemical mechanisms of resistance to tiazofurin. Adv. Enzyme Regul. 24, 67-89 (1985).
110. Grem, J. L. et al. Clinical toxicity associated with tiazofurin. Invest. New Drugs 8, 227-238 (1990).
111. Grifantini, M. Tiazofurine, I. C. N. Pharmaceuticals. Curr. Opin. Investig. Drugs 1, 257-262 (2000).
112. Bi, T. Q. & Che, X. M. Nampt/PBEF/visfatin and cancer. Cancer Biol. Ther. 10, 119-125 (2010).
113. Kim, S. R. et al. Visfatin promotes angiogenesis by activation of extracellular signal-regulated kinase 1/2. Biochem. Biophys. Res. Commun. 357, 150-156 (2007).
114. Garten, A. et al. Nampt and its potential role in inflammation and type 2 diabetes. Handb. Exp. Pharmacol. 203, 147-164 (2011).
115. Hasmann, M. & Schemainda, I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res. 63, 7436-7442 (2003).
116. Watson, M. et al. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1 deficient tumors. Mol. Cell. Biol. 29, 5872-5888 (2009).
117. Lukasova, M., Hanson, J., Tunaru, S. & Offermanns, S. Nicotinic acid (niacin): new lipid-independent mechanisms of action and therapeutic potentials. Trends Pharmacol. Sci. 32, 700-707 (2011).
118. Beauparlant, P. et al. Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777. Anticancer Drugs 20, 346-354 (2009).
119. Drevs, J., Loser, R., Rattel, B. & Esser, N. Antiangiogenic potency of FK866/K22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma. Anticancer Res. 23, 4853-4858 (2003).
120. Kato, H. et al. Efficacy of combining GMX1777 with radiation therapy for human head and neck carcinoma. Clin. Cancer Res. 16, 898-911 (2010).
121. Fleischer, T. C. et al. Chemical proteomics identifies Nampt as the target of CB30865, an orphan cytotoxic compound. Chem. Biol. 17, 659-664 (2010).
122. Holen, K., Saltz, L. B., Hollywood, E., Burk, K. & Hanauske, A. R. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. New Drugs 26, 45-51 (2008).
123. Hovstadius, P. et al. A Phase I study of CHS 828 in patients with solid tumor malignancy. Clin. Cancer Res. 8, 2843-2850 (2002).
124. Ravaud, A. et al. Phase I study and pharmacokinetic of CHS 828, a guanidino-containing compound, administered orally as a single dose every 3 weeks in solid tumours: an ECSG/EORTC study. Eur. J. Cancer 41, 702-707 (2005).
125. von Heideman, A., Berglund, A., Larsson, R. & Nygren, P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother. Pharmacol. 65, 1165-1172 (2010).
126. Billington, R. A., Genazzani, A. A., Travelli, C. & Condorelli, F. NAD depletion by FK866 induces autophagy. Autophagy. 4, 385-387 (2008).
127. Travelli, C. et al. Reciprocal potentiation of the antitumoral activities of FK866, an inhibitor of nicotinamide phosphoribosyltransferase, and etoposide or cisplatin in neuroblastoma cells. J. Pharmacol. Exp. Ther. 338, 829-840 (2011).
128. Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037-2042 (2010).
129. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (Institute of Medicine, National Academy Press, 1998).
130. Clark, J. B. & Pinder, S. Control of the steady-state concentrations of the nicotinamide nucleotides in rat liver. Biochem. J. 114, 321-330 (1969).
131. Deberardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11-20 (2008).
132. Haikal, A. A. Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies. Biomark Med. 4, 241-263 (2010).
133. Lim, J. H. et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1 ?. Mol. Cell 38, 864-878 (2010).
134. Zhong, L. et al. The histone deacetylase sirt6 regulates glucose homeostasis via Hif1 ?. Cell 140, 280-293 (2010).