The emerging immunological role of post-translational modifications by reactive nitrogen species in cancer microenvironment

Frontiers in Immunology

Volumn 5, Issue FEB, 2014, Pages

  De Sanctis, Francesco ^a   Sandri, Sara ^a   Ferrarini, Giovanna ^a   Pagliarello, Irene ^a   Sartoris, Silvia ^a   Ugel, Stefano ^a   Marigo, Ilaria ^b   Molon, Barbara ^c   Bronte, Vincenzo ^a  

^a UNIVERSITY OF VERONA   (Italy)

^b VENETO INSTITUTE OF ONCOLOGY IOV IRCCS   (Italy)

^c VENETIAN INSTITUTE OF MOLECULAR MEDICINE   (Italy)

Author keywords

Cancer; Immune escape; Microenvironment; Nitrotyrosine; RNS

Indexed keywords

3 NITROTYROSINE; ARGINASE; CELECOXIB; CITRULLINE; CURCUMIN; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INDUCIBLE NITRIC OXIDE SYNTHASE; NITRIC OXIDE; ORNITHINE; PHOSPHODIESTERASE V INHIBITOR; REACTIVE NITROGEN SPECIES; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; RESVERATROL;

CANCER GROWTH; DOWN REGULATION; GENE EXPRESSION; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; INFLAMMATION; NEOPLASM; NITRATION; NITROSYLATION; NONHUMAN; PROTEIN DEGRADATION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; TH1 CELL; TH2 CELL; TUMOR GROWTH; TUMOR MICROENVIRONMENT; UPREGULATION;

EID: 84895528474     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2014.00069     Document Type: Review

References (181)

1. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell (2005) 7(3):211-7. doi: 10.1016/j.ccr.2005.02.013.
2. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer (2005) 5(4):263-74. doi:10.1038/nrc1586.
3. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science (2011) 331(6024):1565-70. doi:10.1126/science.1203486.
4. Bronte V, Cingarlini S, Marigo I, De Santo C, Gallina G, Dolcetti L, et al. Leukocyte infiltration in cancer creates an unfavorable environment for antitumor immune responses: a novel target for therapeutic intervention. Immunol Invest (2006) 35(3-4):327-57. doi:10.1080/08820130600754994.
5. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol (2012) 12(4):253-68. doi:10.1038/nri3175.
6. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res (2007) 67(1):425. doi:10.1158/0008-5472.CAN-06-3037.
7. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer cell (2005) 7(5):469-83. doi:10.1016/j.ccr.2005.04.023.
8. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother (2011) 60(10):1419-30. doi:10.1007/s00262-011-1028-0.
9. Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood (2011) 118(8):2254-65. doi:10.1182/blood-2010-12-325753.
10. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity (2010) 32(5):593-604. doi:10.1016/j.immuni.2010.05.007.
11. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol (2010) 22(2):231-7. doi:10.1016/j.coi.2010.01.009.
12. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol (2002) 23(11):549-55. doi:10.1016/S1471-4906(02)02302-5.
13. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest (2007) 117(5):1155-66. doi:10.1172/JCI31422.
14. Mantovani A, Sica A, Allavena P, Garlanda C, Locati M. Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol (2009) 70(5):325-30. doi:10.1016/j.humimm.2009.02.008.
15. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell (2010) 141(1):39-51. doi:10.1016/j.cell.2010.03.014.
16. Burt BM, Rodig SJ, Tilleman TR, Elbardissi AW, Bueno R, Sugarbaker DJ. Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer (2011) 117(22):5234-44. doi:10.1002/cncr.26143.
17. Chung FT, Lee KY, Wang CW, Heh CC, Chan YF, Chen HW, et al. Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer. Int J Cancer (2012) 131(3):E227-35. doi:10.1002/ijc.27403.
18. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol (2011) 11(10):702-11. doi:10.1038/nri3064.
19. Grohmann U, Bronte V. Control of immune response by amino acid metabolism. Immunol Rev (2010) 236:243-64. doi:10.1111/j.1600-065X.2010.00915.x.
20. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res (2004) 64(16):5839-49. doi:10.1158/0008-5472.CAN-04-0465.
21. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol (2006) 176(11):6752-61.
22. Boulland ML, Marquet J, Molinier-Frenkel V, Moller P, Guiter C, Lasoudris F, et al. Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation. Blood (2007) 110(1):220-7. doi:10.1182/blood-2006-07-036210.
23. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res (2010) 70(1):68-77. doi:10.1158/0008-5472.CAN-09-2587.
24. Michel T, Feron O. Nitric oxide synthases: which, where, how, and why? J Clin Invest (1997) 100(9):2146-52. doi:10.1172/JCI119750.
25. Spratt DE, Taiakina V, Palmer M, Guillemette JG. Differential binding of calmodulin domains to constitutive and inducible nitric oxide synthase enzymes. Biochemistry (2007) 46(28):8288-300. doi:10.1021/bi062130b.
26. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol (2005) 5(8):641-54. doi:10.1038/nri1668.
27. Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J (1996) 313(Pt 1):17-29.
28. Heijnen HF, van Donselaar E, Slot JW, Fries DM, Blachard-Fillion B, Hodara R, et al. Subcellular localization of tyrosine-nitrated proteins is dictated by reactive oxygen species generating enzymes and by proximity to nitric oxide synthase. Free Radic Biol Med (2006) 40(11):1903-13. doi:10.1016/j.freeradbiomed.2005.09.006.
29. Dalle-Donne I, Milzani A, Gagliano N, Colombo R, Giustarini D, Rossi R. Molecular mechanisms and potential clinical significance of S-glutathionylation. Antioxid Redox Signal (2008) 10(3):445-73. doi:10.1089/ars.2007.1716.
30. Leon L, Jeannin JF, Bettaieb A. Post-translational modifications induced by nitric oxide (NO): implication in cancer cells apoptosis. Nitric Oxide (2008) 19(2):77-83. doi:10.1016/j.niox.2008.04.014.
31. Bian K, Gao Z, Weisbrodt N, Murad F. The nature of heme/iron-induced protein tyrosine nitration. Proc Natl Acad Sci U S A (2003) 100(10):5712-7. doi:10.1073/pnas.0931291100.
32. Beckman JS, Chen J, Ischiropoulos H, Crow JP. Oxidative chemistry of peroxynitrite. Methods Enzymol (1994) 233:229-40. doi:10.1016/S0076-6879(94)33026-3.
33. Beckman JS, Ischiropoulos H, Zhu L, van der Woerd M, Smith C, Chen J, et al. Kinetics of superoxide dismutase-and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys (1992) 298(2):438-45. doi:10.1016/0003-9861(92)90432-V.
34. Kamisaki Y, Wada K, Bian K, Balabanli B, Davis K, Martin E, et al. An activity in rat tissues that modifies nitrotyrosine-containing proteins. Proc Natl Acad Sci U S A (1998) 95(20):11584-9. doi:10.1073/pnas.95.20.11584.
35. Kuo WN, Kanadia RN, Shanbhag VP, Toro R. Denitration of peroxynitrite-treated proteins by 'protein nitratases' from rat brain and heart. Mol Cell Biochem (1999) 201(1-2):11-6. doi:10.1023/A:1007024126947.
36. Kuo WN, Kanadia RN, Shanbhag VP. Denitration of peroxynitrite-treated proteins by "protein nitratases" from dog prostate. Biochem Mol Biol Int (1999) 47(6):1061-7.
37. Kang M, Akbarali HI. Denitration of L-type calcium channel. FEBS Lett (2008) 582(20):3033-6. doi:10.1016/j.febslet.2008.07.042.
38. Smallwood HS, Lourette NM, Boschek CB, Bigelow DJ, Smith RD, Pasa-Tolic L, et al. Identification of a denitrase activity against calmodulin in activated macrophages using high-field liquid chromatography-FTICR mass spectrometry. Biochemistry (2007) 46(37):10498-505. doi:10.1021/bi7009713.
39. Koeck T, Fu X, Hazen SL, Crabb JW, Stuehr DJ, Aulak KS. Rapid and selective oxygen-regulated protein tyrosine denitration and nitration in mitochondria. J Biol Chem (2004) 279(26):27257-62. doi:10.1074/jbc.M401586200.
40. Ischiropoulos H. Biological selectivity and functional aspects of protein tyrosine nitration. Biochem Biophys Res Commun (2003) 305(3):776-83. doi:10.1016/S0006-291X(03)00814-3.
41. Gole MD, Souza JM, Choi I, Hertkorn C, Malcolm S, Foust RF III, et al. Plasma proteins modified by tyrosine nitration in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol (2000) 278(5):L961-7.
42. Knapp LT, Kanterewicz BI, Hayes EL, Klann E. Peroxynitrite-induced tyrosine nitration and inhibition of protein kinase C. Biochem Biophys Res Commun (2001) 286(4):764-70. doi:10.1006/bbrc.2001.5448.
43. Cassina AM, Hodara R, Souza JM, Thomson L, Castro L, Ischiropoulos H, et al. Cytochrome c nitration by peroxynitrite. J Biol Chem (2000) 275(28):21409-15. doi:10.1074/jbc.M909978199.
44. Vadseth C, Souza JM, Thomson L, Seagraves A, Nagaswami C, Scheiner T, et al. Pro-thrombotic state induced by post-translational modification of fibrinogen by reactive nitrogen species. J Biol Chem (2004) 279(10):8820-6. doi:10.1074/jbc.M306101200.
45. Balafanova Z, Bolli R, Zhang J, Zheng Y, Pass JM, Bhatnagar A, et al. Nitric oxide (NO) induces nitration of protein kinase Cepsilon (PKCepsilon), facilitating PKCepsilon translocation via enhanced PKCepsilon-RACK2 interactions: a novel mechanism of no-triggered activation of PKCepsilon. J Biol Chem (2002) 277(17):15021-7. doi:10.1074/jbc.M112451200.
46. Ji Y, Neverova I, Van Eyk JE, Bennett BM. Nitration of tyrosine 92 mediates the activation of rat microsomal glutathione S-transferase by peroxynitrite. J Biol Chem (2006) 281(4):1986-91. doi:10.1074/jbc.M509480200.
47. Bentz BG, Haines GK III, Radosevich JA. Increased protein nitrosylation in head and neck squamous cell carcinogenesis. Head Neck (2000) 22(1):64-70. doi:10.1002/(SICI)1097-0347(200001)22:1<::AID-HED10>3.3.CO;2-A.
48. Fitzpatrick B, Mehibel M, Cowen RL, Stratford IJ. iNOS as a therapeutic target for treatment of human tumors. Nitric Oxide (2008) 19(2):217-24. doi:10.1016/j.niox.2008.05.001.
49. Iyer AK, Azad N, Wang L, Rojanasakul Y. Role of S-nitrosylation in apoptosis resistance and carcinogenesis. Nitric Oxide (2008) 19(2):146-51. doi:10.1016/j.niox.2008.04.019.
50. Leon-Bollotte L, Subramaniam S, Cauvard O, Plenchette-Colas S, Paul C, Godard C, et al. S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. Gastroenterology (2011) 140(7):2009-18. doi:10.1053/j.gastro.2011.02.053.
51. Calmels S, Hainaut P, Ohshima H. Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. Cancer Res (1997) 57(16):3365-9.
52. Lima B, Lam GK, Xie L, Diesen DL, Villamizar N, Nienaber J, et al. Endogenous S-nitrosothiols protect against myocardial injury. Proc Natl Acad Sci U S A (2009) 106(15):6297-302. doi:10.1073/pnas.0901043106.
53. Liu L, Xu-Welliver M, Kanugula S, Pegg AE. Inactivation and degradation of O(6)-alkylguanine-DNA alkyltransferase after reaction with nitric oxide. Cancer Res (2002) 62(11):3037-43.
54. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer (2007) 7(12):961-7. doi:10.1038/nrc2254.
55. Tripathi DN, Chowdhury R, Trudel LJ, Tee AR, Slack RS, Walker CL, et al. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proc Natl Acad Sci U S A (2013) 110(32):E2950-7. doi:10.1073/pnas.1307736110.
56. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev (2007) 87(1):245-313. doi:10.1152/physrev.00044.2005.
57. Brandes RP, Schroder K. Differential vascular functions of Nox family NADPH oxidases. Curr Opin Lipidol (2008) 19(5):513-8. doi:10.1097/MOL.0b013e32830c91e3.
58. Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol (2009) 182(9):5693-701. doi:10.4049/jimmunol.0900092.
59. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med (2008) 205(10):2235-49. doi:10.1084/jem.20080132.
60. Manea A, Tanase LI, Raicu M, Simionescu M. Jak/STAT signaling pathway regulates nox1 and nox4-based NADPH oxidase in human aortic smooth muscle cells. Arterioscler Thromb Vasc Biol (2010) 30(1):105-12. doi:10.1161/ATVBAHA.109.193896.
61. Raad H, Paclet MH, Boussetta T, Kroviarski Y, Morel F, Quinn MT, et al. Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67phox, and p47phox. FASEB J (2009) 23(4):1011-22. doi:10.1096/fj.08-114553.
62. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science (1995) 267(5203):1485-8. doi:10.1126/science.7878466.
63. Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci (2004) 75(6):639-53. doi:10.1016/j.lfs.2003.10.042.
64. Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide (2010) 23(2):75-93. doi:10.1016/j.niox.2010.04.007.
65. Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, et al. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci U S A (1993) 90(20):9730-4. doi:10.1073/pnas.90.20.9730.
66. Kristof AS, Marks-Konczalik J, Moss J. Mitogen-activated protein kinases mediate activator protein-1-dependent human inducible nitric-oxide synthase promoter activation. J Biol Chem (2001) 276(11):8445-52. doi:10.1074/jbc.M009563200.
67. Galea E, Feinstein DL. Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP. FASEB J (1999) 13(15):2125-37.
68. Mullet D, Fertel RH, Kniss D, Cox GW. An increase in intracellular cyclic AMP modulates nitric oxide production in IFN-gamma-treated macrophages. J Immunol (1997) 158(2):897-904.
69. Park KS, Guo Z, Shao L, Du Q, Geller DA. A far-upstream Oct-1 motif regulates cytokine-induced transcription of the human inducible nitric oxide synthase gene. J Mol Biol (2009) 390(4):595-603. doi:10.1016/j.jmb.2009.05.036.
70. Perrella MA, Yoshizumi M, Fen Z, Tsai JC, Hsieh CM, Kourembanas S, et al. Transforming growth factor-beta 1, but not dexamethasone, down-regulates nitric-oxide synthase mRNA after its induction by interleukin-1 beta in rat smooth muscle cells. J Biol Chem (1994) 269(20):14595-600.
71. Rodriguez-Pascual F, Hausding M, Ihrig-Biedert I, Furneaux H, Levy AP, Forstermann U, et al. Complex contribution of the 3'-untranslated region to the expressional regulation of the human inducible nitric-oxide synthase gene. Involvement of the RNA-binding protein HuR. J Biol Chem (2000) 275(34):26040-9. doi:10.1074/jbc.M910460199.
72. Walker G, Pfeilschifter J, Kunz D. Mechanisms of suppression of inducible nitric-oxide synthase (iNOS) expression in interferon (IFN)-gamma-stimulated RAW 264.7 cells by dexamethasone. Evidence for glucocorticoid-induced degradation of iNOS protein by calpain as a key step in post-transcriptional regulation. J Biol Chem (1997) 272(26):16679-87.
73. Felley-Bosco E, Bender FC, Courjault-Gautier F, Bron C, Quest AF. Caveolin-1 down-regulates inducible nitric oxide synthase via the proteasome pathway in human colon carcinoma cells. Proc Natl Acad Sci U S A (2000) 97(26):14334-9. doi:10.1073/pnas.250406797.
74. Mitani T, Terashima M, Yoshimura H, Nariai Y, Tanigawa Y. TGF-beta1 enhances degradation of IFN-gamma-induced iNOS protein via proteasomes in RAW 264.7 cells. Nitric Oxide (2005) 13(1):78-87. doi:10.1016/j.niox.2005.05.001.
75. Paukkeri EL, Leppanen T, Sareila O, Vuolteenaho K, Kankaanranta H, Moilanen E. PPARalpha agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS-treated macrophages. Br J Pharmacol (2007) 152(7):1081-91. doi:10.1038/sj.bjp.0707477.
76. Kuang Z, Lewis RS, Curtis JM, Zhan Y, Saunders BM, Babon JJ, et al. The SPRY domain-containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation. J Cell Biol (2010) 190(1):129-41. doi:10.1083/jcb.200912087.
77. Nishiya T, Matsumoto K, Maekawa S, Kajita E, Horinouchi T, Fujimuro M, et al. Regulation of inducible nitric-oxide synthase by the SPRY domain-and SOCS box-containing proteins. J Biol Chem (2011) 286(11):9009-19. doi:10.1074/jbc.M110.190678.
78. Iyer R, Jenkinson CP, Vockley JG, Kern RM, Grody WW, Cederbaum S. The human arginases and arginase deficiency. J Inherit Metab Dis (1998) 21(Suppl 1):86-100. doi:10.1023/A:1005383919335.
79. Gray MJ, Poljakovic M, Kepka-Lenhart D, Morris SM Jr. Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta. Gene (2005) 353(1):98-106. doi:10.1016/j.gene.2005.04.004.
80. Pauleau AL, Rutschman R, Lang R, Pernis A, Watowich SS, Murray PJ. Enhancer-mediated control of macrophage-specific arginase I expression. J Immunol (2004) 172(12):7565-73.
81. Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med (2005) 202(7):931-9. doi:10.1084/jem.20050715.
82. Sharda DR, Yu S, Ray M, Squadrito ML, De Palma M, Wynn TA, et al. Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J Immunol (2011) 187(5):2181-92. doi:10.4049/jimmunol.1003460.
83. Santhanam L, Lim HK, Miriel V, Brown T, Patel M, Balanson S, et al. Inducible NO synthase dependent S-nitrosylation and activation of arginase1 contribute to age-related endothelial dysfunction. Circ Res (2007) 101(7):692-702. doi:10.1161/CIRCRESAHA.107.157727.
84. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell (2010) 40(2):294-309. doi:10.1016/j.molcel.2010.09.022.
85. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med (2010) 207(11):2439-53. doi:10.1084/jem.20100587.
86. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer (2003) 3(10):721-32. doi:10.1038/nrc1187.
87. Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med (1995) 182(6):1683-93. doi:10.1084/jem.182.6.1683.
88. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res (2010) 70(19):7465-75. doi:10.1158/0008-5472.CAN-10-1439.
89. Metzen E, Zhou J, Jelkmann W, Fandrey J, Brune B. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell (2003) 14(8):3470-81. doi:10.1091/mbc.E02-12-0791.
90. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity (2010) 32(6):790-802. doi:10.1016/j.immuni.2010.05.010.
91. Allavena P, Bianchi G, Zhou D, van Damme J, Jilek P, Sozzani S, et al. Induction of natural killer cell migration by monocyte chemotactic protein-1,-2 and-3. Eur J Immunol (1994) 24(12):3233-6. doi:10.1002/eji.1830241249.
92. van de Laar L, Coffer PJ, Woltman AM. Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy. Blood (2012) 119(15):3383-93. doi:10.1182/blood-2011-11-370130.
93. Wu L, Du H, Li Y, Qu P, Yan C. Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis. Am J Pathol (2011) 179(4):2131-41. doi:10.1016/j.ajpath.2011.06.028.
94. Martin E, Nathan C, Xie QW. Role of interferon regulatory factor 1 in induction of nitric oxide synthase. J Exp Med (1994) 180(3):977-84. doi:10.1084/jem.180.3.977.
95. Hooper LV, Stappenbeck TS, Hong CV, Gordon JI. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol (2003) 4(3):269-73. doi:10.1038/ni888.
96. Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes JM, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood (2005) 105(6):2549-56. doi:10.1182/blood-2004-07-2521.
97. Munder M. Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol (2009) 158(3):638-51. doi:10.1111/j.1476-5381.2009.00291.x.
98. Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JF Jr, Cheever AW, et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest (2006) 116(7):2044-55. doi:10.1172/JCI27727.
99. Hecker M, Nematollahi H, Hey C, Busse R, Racke K. Inhibition of arginase by NG-hydroxy-L-arginine in alveolar macrophages: implications for the utilization of L-arginine for nitric oxide synthesis. FEBS Lett (1995) 359(2-3):251-4. doi:10.1016/0014-5793(95)00039-C.
100. Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol (2009) 9(4):447-53. doi:10.1016/j.coph.2009.04.008.
101. Boutard V, Havouis R, Fouqueray B, Philippe C, Moulinoux JP, Baud L. Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity. J Immunol (1995) 155(4):2077-84.
102. Chen YH, Layne MD, Chung SW, Ejima K, Baron RM, Yet SF, et al. Elk-3 is a transcriptional repressor of nitric-oxide synthase 2. J Biol Chem (2003) 278(41):39572-7. doi:10.1074/jbc.M308179200.
103. Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest (2006) 116(10):2777-90. doi:10.1172/JCI28828.
104. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol (2009) 9(3):162-74. doi:10.1038/nri2506.
105. Brito C, Naviliat M, Tiscornia AC, Vuillier F, Gualco G, Dighiero G, et al. Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. J Immunol (1999) 162(6):3356-66.
106. Aulak KS, Miyagi M, Yan L, West KA, Massillon D, Crabb JW, et al. Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci U S A (2001) 98(21):12056-61. doi:10.1073/pnas.221269198.
107. Moulian N, Truffault F, Gaudry-Talarmain YM, Serraf A, Berrih-Aknin S. In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation. Blood (2001) 97(11):3521-30. doi:10.1182/blood.V97.11.3521.
108. Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, et al. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest (2011) 121(10):4015-29. doi:10.1172/JCI45862.
109. Abello N, Kerstjens HA, Postma DS, Bischoff R. Protein tyrosine nitration: selectivity, physicochemical and biological consequences, denitration, and proteomics methods for the identification of tyrosine-nitrated proteins. J Proteome Res (2009) 8(7):3222-38. doi:10.1021/pr900039c.
110. Birnboim HC, Lemay AM, Lam DK, Goldstein R, Webb JR. Cutting edge: MHC class II-restricted peptides containing the inflammation-associated marker 3-nitrotyrosine evade central tolerance and elicit a robust cell-mediated immune response. J Immunol (2003) 171(2):528-32.
111. Hardy LL, Wick DA, Webb JR. Conversion of tyrosine to the inflammation-associated analog 3'-nitrotyrosine at either TCR-or MHC-contact positions can profoundly affect recognition of the MHC class I-restricted epitope of lymphocytic choriomeningitis virus glycoprotein 33 by CD8 T cells. J Immunol (2008) 180(9):5956-62.
112. Madhurantakam C, Duru AD, Sandalova T, Webb JR, Achour A. Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex. PLoS One (2012) 7(3):e32805. doi:10.1371/journal.pone.0032805.
113. Sandhu JK, Privora HF, Wenckebach G, Birnboim HC. Neutrophils, nitric oxide synthase, and mutations in the mutatect murine tumor model. Am J Pathol (2000) 156(2):509-18. doi:10.1016/S0002-9440(10)64755-4.
114. Herzog J, Maekawa Y, Cirrito TP, Illian BS, Unanue ER. Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells. Proc Natl Acad Sci U S A (2005) 102(22):7928-33. doi:10.1073/pnas.0502255102.
115. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med (2007) 13(7):828-35. doi:10.1038/nm1609.
116. Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol (2010) 184(6):3106-16. doi:10.4049/jimmunol.0902661.
117. Kasic T, Colombo P, Soldani C, Wang CM, Miranda E, Roncalli M, et al. Modulation of human T-cell functions by reactive nitrogen species. Eur J Immunol (2011) 41(7):1843-9. doi:10.1002/eji.201040868.
118. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med (2011) 208(10):1949-62. doi:10.1084/jem.20101956.
119. Curnock AP, Logan MK, Ward SG. Chemokine signalling: pivoting around multiple phosphoinositide 3-kinases. Immunology (2002) 105(2):125-36. doi:10.1046/j.1365-2567.2002.01345.x.
120. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med (2006) 354(6):610-21. doi:10.1056/NEJMra052723.
121. Viola A, Luster AD. Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol (2008) 48:171-97. doi:10.1146/annurev.pharmtox.48.121806.154841.
122. Mortier A, Van Damme J, Proost P. Overview of the mechanisms regulating chemokine activity and availability. Immunol Lett (2012) 145(1-2):2-9. doi:10.1016/j.imlet.2012.04.015.
123. Moelants EA, Mortier A, Van Damme J, Proost P. In vivo regulation of chemokine activity by post-translational modification. Immunol Cell Biol (2013) 91(6):402-7. doi:10.1038/icb.2013.16.
124. Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med (2005) 201(8):1257-68. doi:10.1084/jem.20042028.
125. Nemirovskiy OV, Radabaugh MR, Aggarwal P, Funckes-Shippy CL, Mnich SJ, Meyer DM, et al. Plasma 3-nitrotyrosine is a biomarker in animal models of arthritis: pharmacological dissection of iNOS' role in disease. Nitric Oxide (2009) 20(3):150-6. doi:10.1016/j.niox.2008.12.005.
126. Butterfield DA, Reed T, Sultana R. Roles of 3-nitrotyrosine-and 4-hydroxynonenal-modified brain proteins in the progression and pathogenesis of Alzheimer's disease. Free Radic Res (2011) 45(1):59-72. doi:10.3109/10715762.2010.520014.
127. Sokolovsky M, Riordan JF, Vallee BL. Conversion of 3-nitrotyrosine to 3-aminotyrosine in peptides and proteins. Biochem Biophys Res Commun (1967) 27(1):20-5. doi:10.1016/S0006-291X(67)80033-0.
128. Tsikas D, Caidahl K. Recent methodological advances in the mass spectrometric analysis of free and protein-associated 3-nitrotyrosine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci (2005) 814(1):1-9. doi:10.1016/j.jchromb.2004.10.003.
129. Frost MT, Halliwell B, Moore KP. Analysis of free and protein-bound nitrotyrosine in human plasma by a gas chromatography/mass spectrometry method that avoids nitration artifacts. Biochem J (2000) 345(Pt 3):453-8. doi:10.1042/0264-6021:3450453.
130. Bigelow DJ, Qian WJ. Quantitative proteome mapping of nitrotyrosines. Methods Enzymol (2008) 440:191-205. doi:10.1016/S0076-6879(07)00811-7.
131. Nuriel T, Deeb RS, Hajjar DP, Gross SS. Protein 3-nitrotyrosine in complex biological samples: quantification by high-pressure liquid chromatography/electrochemical detection and emergence of proteomic approaches for unbiased identification of modification sites. Methods Enzymol (2008) 441:1-17. doi:10.1016/S0076-6879(08)01201-9.
132. Radi R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci U S A (2004) 101(12):4003-8. doi:10.1073/pnas.0307446101.
133. Yamakura F, Ikeda K. Modification of tryptophan and tryptophan residues in proteins by reactive nitrogen species. Nitric Oxide (2006) 14(2):152-61. doi:10.1016/j.niox.2005.07.009.
134. Ikeda K, Yukihiro Hiraoka B, Iwai H, Matsumoto T, Mineki R, Taka H, et al. Detection of 6-nitrotryptophan in proteins by Western blot analysis and its application for peroxynitrite-treated PC12 cells. Nitric Oxide (2007) 16(1):18-28. doi:10.1016/j.niox.2006.04.263.
135. Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer (2006) 6(7):521-34. doi:10.1038/nrc1910.
136. Rahat MA, Hemmerlein B. Macrophage-tumor cell interactions regulate the function of nitric oxide. Front Physiol (2013) 4:144. doi:10.3389/fphys.2013.00144.
137. Zhang W, He XJ, Ma YY, Wang HJ, Xia YJ, Zhao ZS, et al. Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients. Hum Pathol (2011) 42(9):1275-82. doi:10.1016/j.humpath.2010.09.020.
138. Ekmekcioglu S, Ellerhorst JA, Prieto VG, Johnson MM, Broemeling LD, Grimm EA. Tumor iNOS predicts poor survival for stage III melanoma patients. Int J Cancer (2006) 119(4):861-6. doi:10.1002/ijc.21767.
139. Eggen T, Sager G, Arnes M, Pettersen I, Orbo A. Expression of iNOS-a favourable prognostic marker for early-stage carcinoma of the uterine cervix. Anticancer Res (2011) 31(6):2319-25.
140. Raspollini MR, Amunni G, Villanucci A, Boddi V, Baroni G, Taddei A, et al. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in ovarian cancer: correlation with clinical outcome. Gynecol Oncol (2004) 92(3):806-12. doi:10.1016/j.ygyno.2003.12.023.
141. Oka K, Suzuki Y, Iida H, Nakano T. Pd-ECGF positivity correlates with better survival, while iNOS has no predictive value for cervical carcinomas treated with radiotherapy. Int J Radiat Oncol Biol Phys (2003) 57(1):217-21. doi:10.1016/S0360-3016(03)00436-X.
142. Loibl S, von Minckwitz G, Weber S, Sinn HP, Schini-Kerth VB, Lobysheva I, et al. Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy. Cancer (2002) 95(6):1191-8. doi:10.1002/cncr.10817.
143. Cobbs CS, Brenman JE, Aldape KD, Bredt DS, Israel MA. Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res (1995) 55(4):727-30.
144. Daniliuc S, Bitterman H, Rahat MA, Kinarty A, Rosenzweig D, Lahat N. Hypoxia inactivates inducible nitric oxide synthase in mouse macrophages by disrupting its interaction with alpha-actinin 4. J Immunol (2003) 171(6):3225-32.
145. Beckmann JS, Ye YZ, Anderson PG, Chen J, Accavitti MA, Tarpey MM, et al. Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol Chem Hoppe Seyler (1994) 375(2):81-8. doi:10.1515/bchm3.1994.375.2.81.
146. Raber P, Ochoa AC, Rodriguez PC. Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest (2012) 41(6-7):614-34. doi:10.3109/08820139.2012.680634.
147. Gochman E, Mahajna J, Shenzer P, Dahan A, Blatt A, Elyakim R, et al. The expression of iNOS and nitrotyrosine in colitis and colon cancer in humans. Acta Histochem (2012) 114(8):827-35. doi:10.1016/j.acthis.2012.02.004.
148. Li LG, Xu HM. Inducible nitric oxide synthase, nitrotyrosine and apoptosis in gastric adenocarcinomas and their correlation with a poor survival. World J Gastroenterol (2005) 11(17):2539-44.
149. Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, et al. Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res (2006) 12(4):1201-7. doi:10.1158/1078-0432.CCR-05-1269.
150. Kinnula VL, Torkkeli T, Kristo P, Sormunen R, Soini Y, Paakko P, et al. Ultrastructural and chromosomal studies on manganese superoxide dismutase in malignant mesothelioma. Am J Respir Cell Mol Biol (2004) 31(2):147-53. doi:10.1165/rcmb.2003-0409OC.
151. Nakamura Y, Yasuoka H, Zuo H, Takamura Y, Miyauchi A, Nakamura M, et al. Nitric oxide in papillary thyroid carcinoma: induction of vascular endothelial growth factor D and correlation with lymph node metastasis. J Clin Endocrinol Metab (2006) 91(4):1582-5. doi:10.1210/jc.2005-1790.
152. Vickers SM, MacMillan-Crow LA, Green M, Ellis C, Thompson JA. Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch Surg (1999) 134(3):245-51. doi:10.1001/archsurg.134.3.245.
153. Cobbs CS, Samanta M, Harkins LE, Gillespie GY, Merrick BA, MacMillan-Crow LA. Evidence for peroxynitrite-mediated modifications to p53 in human gliomas: possible functional consequences. Arch Biochem Biophys (2001) 394(2):167-72. doi:10.1006/abbi.2001.2540.
154. Cobbs CS, Whisenhunt TR, Wesemann DR, Harkins LE, Van Meir EG, Samanta M. Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells. Cancer Res (2003) 63(24):8670-3.
155. Masri FA, Comhair SA, Koeck T, Xu W, Janocha A, Ghosh S, et al. Abnormalities in nitric oxide and its derivatives in lung cancer. Am J Respir Crit Care Med (2005) 172(5):597-605. doi:10.1164/rccm.200411-1523OC.
156. Bentz BG, Haines GK III, Lingen MW, Pelzer HJ, Hanson DG, Radosevich JA. Nitric oxide synthase type 3 is increased in squamous hyperplasia, dysplasia, and squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol (1999) 108(8):781-7.
157. Kojima M, Morisaki T, Tsukahara Y, Uchiyama A, Matsunari Y, Mibu R, et al. Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue. J Surg Oncol (1999) 70(4):222-9. doi:10.1002/(SICI)1096-9098(199904)70:4<::AID-JSO5>3.0.CO;2-G.
158. Kitano H, Kitanishi T, Nakanishi Y, Suzuki M, Takeuchi E, Yazawa Y, et al. Expression of inducible nitric oxide synthase in human thyroid papillary carcinomas. Thyroid (1999) 9(2):113-7. doi:10.1089/thy.1999.9.113.
159. Ehsan A, Sommer F, Schmidt A, Klotz T, Koslowski J, Niggemann S, et al. Nitric oxide pathways in human bladder carcinoma. The distribution of nitric oxide synthases, soluble guanylyl cyclase, cyclic guanosine monophosphate, and nitrotyrosine. Cancer (2002) 95(11):2293-301. doi:10.1002/cncr.10942.
160. Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B. Differences in oxidative stress dependence between gastric adenocarcinoma subtypes. World J Gastroenterol (2006) 12(7):1005-12.
161. Soini Y, Kallio JP, Hirvikoski P, Helin H, Kellokumpu-Lehtinen P, Kang SW, et al. Oxidative/nitrosative stress and peroxiredoxin 2 are associated with grade and prognosis of human renal carcinoma. APMIS (2006) 114(5):329-37. doi:10.1111/j.1600-0463.2006.apm_315.x.
162. Karihtala P, Soini Y, Vaskivuo L, Bloigu R, Puistola U. DNA adduct 8-hydroxydeoxyguanosine, a novel putative marker of prognostic significance in ovarian carcinoma. Int J Gynecol Cancer (2009) 19(6):1047-51. doi:10.1111/IGC.0b013e3181ad0f0d.
163. Pylvas M, Puistola U, Kauppila S, Soini Y, Karihtala P. Oxidative stress-induced antioxidant enzyme expression is an early phenomenon in ovarian carcinogenesis. Eur J Cancer (2010) 46(9):1661-7. doi:10.1016/j.ejca.2010.02.006.
164. Yamanaka Y, Friess H, Buchler M, Beger HG, Uchida E, Onda M, et al. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res (1993) 53(21):5289-96.
165. Aktan B, Taysi S, Gumustekin K, Ucuncu H, Memisogullari R, Save K, et al. Effect of macrolide antibiotics on nitric oxide synthase and xanthine oxidase activities, and malondialdehyde level in erythrocyte of the guinea pigs with experimental otitis media with effusion. Pol J Pharmacol (2003) 55(6):1105-10.
166. Mariotto S, Cuzzolin L, Adami A, Del Soldato P, Suzuki H, Benoni G. Effect of a new non-steroidal anti-inflammatory drug, nitroflurbiprofen, on the expression of inducible nitric oxide synthase in rat neutrophils. Br J Pharmacol (1995) 115(2):225-6. doi:10.1111/j.1476-5381.1995.tb15867.x.
167. Griscavage JM, Hobbs AJ, Ignarro LJ. Negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds. Adv Pharmacol (1995) 34:215-34. doi:10.1016/S1054-3589(08)61088-1.
168. De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, Del Soldato P, et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U S A (2005) 102(11):4185-90. doi:10.1073/pnas.0409783102.
169. Hickman HD, Reynoso GV, Ngudiankama BF, Rubin EJ, Magadan JG, Cush SS, et al. Anatomically restricted synergistic antiviral activities of innate and adaptive immune cells in the skin. Cell Host Microbe (2013) 13(2):155-68. doi:10.1016/j.chom.2013.01.004.
170. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res (2007) 67(9):4507-13. doi:10.1158/0008-5472.CAN-06-4174.
171. Talmadge JE, Hood KC, Zobel LC, Shafer LR, Coles M, Toth B. Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. Int Immunopharmacol (2007) 7(2):140-51. doi:10.1016/j.intimp.2006.09.021.
172. Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Aerts JG, et al. COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer (2010) 10:464. doi:10.1186/1471-2407-10-464.
173. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med (2006) 203(12):2691-702. doi:10.1084/jem.20061104.
174. Sikora AG, Gelbard A, Davies MA, Sano D, Ekmekcioglu S, Kwon J, et al. Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemotherapy. Clin Cancer Res (2010) 16(6):1834-44. doi:10.1158/1078-0432.CCR-09-3123.
175. Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res (2010) 16(6):1812-23. doi:10.1158/1078-0432.CCR-09-3272.
176. Burkitt MJ, Duncan J. Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action. Arch Biochem Biophys (2000) 381(2):253-63. doi:10.1006/abbi.2000.1973.
177. Hsieh TC, Wang Z, Hamby CV, Wu JM. Inhibition of melanoma cell proliferation by resveratrol is correlated with upregulation of quinone reductase 2 and p53. Biochem Biophys Res Commun (2005) 334(1):223-30. doi:10.1016/j.bbrc.2005.06.073.
178. Bishayee A. Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res (Phila) (2009) 2(5):409-18. doi:10.1158/1940-6207.CAPR-08-0160.
179. Zheng M, Ekmekcioglu S, Walch ET, Tang CH, Grimm EA. Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells. Melanoma Res (2004) 14(3):165-71. doi:10.1097/01.cmr.0000129374.76399.19.
180. Du Q, Hu B, An HM, Shen KP, Xu L, Deng S, et al. Synergistic anticancer effects of curcumin and resveratrol in Hepa1-6 hepatocellular carcinoma cells. Oncol Rep (2013) 29(5):1851-8. doi:10.3892/or.2013.2310.
181. Majumdar AP, Banerjee S, Nautiyal J, Patel BB, Patel V, Du J, et al. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr Cancer (2009) 61(4):544-53. doi:10.1080/01635580902752262.