Cellular and Molecular Life Sciences

, Volume 69, Issue 14, pp 2435–2442 | Cite as

Targeting NADPH oxidases for the treatment of cancer and inflammation

  • Michael Y. Bonner
  • Jack L. ArbiserEmail author
Multi-author review


NADPH oxidases are a family of oxidases that utilize molecular oxygen to generate hydrogen peroxide and superoxide, thus indicating physiological functions of these highly reactive and short-lived species. The regulation of these NADPH oxidases (nox) enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. While the complexity of the nox family (Nox1–5, Duox1, 2) is daunting, the complexity also allows for targeting of NADPH oxidases in disease states. In this review, we discuss which inflammatory and malignant disorders can be targeted by nox inhibitors, as well as clinical experience in the use of such inhibitors.


NADPH oxidase Lymphoma Melanoma Hemangioma Wilms tumor 1 Triphenylmethanes Fulvenes 



Supported by NIAMS Grants RO1AR 47901 and RO1 AR 050727 to J.L.A, and Emory Skin Disease Research Core Center P30 AR 42687


  1. 1.
    Al DR, Powell J, McCuaig C, Kokta V (2010) Differentiation of vascular tumors from vascular malformations by expression of Wilms tumor 1 gene: evaluation of 126 cases. J Am Acad Dermatol 63:1052–1057CrossRefGoogle Scholar
  2. 2.
    Arbiser JL, Govindarajan B, Bai X, Onda H, Kazlauskas A, Lim SD, Amin MB, Claesson-Welsh L (2002) Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis. Am J Pathol 161:781–786PubMedCrossRefGoogle Scholar
  3. 3.
    Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J (1997) Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci USA 94:861–866PubMedCrossRefGoogle Scholar
  4. 4.
    Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD (2002) Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA 99:715–720PubMedCrossRefGoogle Scholar
  5. 5.
    Balasubramanian A, Ganju RK, Groopman JE (2003) Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes. J Biol Chem 278:35755–35766PubMedCrossRefGoogle Scholar
  6. 6.
    Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313PubMedCrossRefGoogle Scholar
  7. 7.
    Bhandarkar SS, Jaconi M, Fried LE, Bonner MY, Lefkove B, Govindarajan B, Perry BN, Parhar R, Mackelfresh J, Sohn A, Stouffs M, Knaus U, Yancopoulos G, Reiss Y, Benest AV, Augustin HG, Arbiser JL (2009) Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice. J Clin Invest 119:2359–2365PubMedGoogle Scholar
  8. 8.
    Block K, Gorin Y, Hoover P, Williams P, Chelmicki T, Clark RA, Yoneda T, Abboud HE (2007) NAD(P)H oxidases regulate HIF-2alpha protein expression. J Biol Chem 282:8019–8026PubMedCrossRefGoogle Scholar
  9. 9.
    Boivin B, Zhang S, Arbiser JL, Zhang ZY, Tonks NK (2008) A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells. Proc Natl Acad Sci USA 105:9959–9964PubMedCrossRefGoogle Scholar
  10. 10.
    Brar SS, Kennedy TP, Sturrock AB, Huecksteadt TP, Quinn MT, Whorton AR, Hoidal JR (2002) An NAD(P)H oxidase regulates growth and transcription in melanoma cells. Am J Physiol Cell Physiol 282:C1212–C1224PubMedGoogle Scholar
  11. 11.
    Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS (2008) The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA 105:9035–9040PubMedCrossRefGoogle Scholar
  12. 12.
    Cerimele F, Battle T, Lynch R, Frank DA, Murad E, Cohen C, Macaron N, Sixbey J, Smith K, Watnick RS, Eliopoulos A, Shehata B, Arbiser JL (2005) Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt’s lymphoma. Proc Natl Acad Sci USA 102:175–179PubMedCrossRefGoogle Scholar
  13. 13.
    Cerimele F, Brown LF, Bravo F, Ihler GM, Kouadio P, Arbiser JL (2003) Infectious angiogenesis: Bartonella bacilliformis infection results in endothelial production of angiopoietin-2 and epidermal production of vascular endothelial growth factor. Am J Pathol 163:1321–1327PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen C, Zavala-Pompa A, Sequeira JH, Shoji M, Sexton DG, Cotsonis G, Cerimele F, Govindarajan B, Macaron N, Arbiser JL (2002) Mitogen-activated protein kinase activation is an early event in melanoma progression. Clin Cancer Res 8:3728–3733PubMedGoogle Scholar
  15. 15.
    Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852PubMedCrossRefGoogle Scholar
  16. 16.
    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147PubMedCrossRefGoogle Scholar
  17. 17.
    Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, Woodman SE, Calderone TC, Ju Z, Lazar AJ, Prieto VG, Aldape K, Mills GB, Gershenwald JE (2009) Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 15:7538–7546PubMedCrossRefGoogle Scholar
  18. 18.
    De SC, De SP, Di MG, Venier A, Cerimele D, Serri F (1989) Reactive oxygen species production in circulating polymorphonuclear leukocytes in psoriasis. Acta Derm Venereol Suppl (Stockh) 146:50–52Google Scholar
  19. 19.
    Dudnakova T, Spraggon L, Slight J, Hastie N (2010) Actin: a novel interaction partner of WT1 influencing its cell dynamic properties. Oncogene 29:1085–1092PubMedCrossRefGoogle Scholar
  20. 20.
    Fried L, Arbiser JL (2008) The reactive oxygen-driven tumor: relevance to melanoma. Pigment Cell Melanoma Res 21:117–122PubMedCrossRefGoogle Scholar
  21. 21.
    Garrido-Urbani S, Jemelin S, Deffert C, Carnesecchi S, Basset O, Szyndralewiez C, Heitz F, Page P, Montet X, Michalik L, Arbiser J, Ruegg C, Krause KH, Imhof B (2011) Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARalpha mediated mechanism. PLoS ONE 6:e14665PubMedCrossRefGoogle Scholar
  22. 22.
    Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, Greenberg RA, Flaherty KT, Rathmell WK, Keith B, Simon MC, Nathanson KL (2008) HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14:435–446PubMedCrossRefGoogle Scholar
  23. 23.
    Govindarajan B, Bai X, Cohen C, Zhong H, Kilroy S, Louis G, Moses M, Arbiser JL (2003) Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling. J Biol Chem 278:9790–9795PubMedCrossRefGoogle Scholar
  24. 24.
    Govindarajan B, Klafter R, Miller MS, Mansur C, Mizesko M, Bai X, LaMontagne K Jr, Arbiser JL (2002) Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase. Mol Med 8:1–8PubMedCrossRefGoogle Scholar
  25. 25.
    Govindarajan B, Shah A, Cohen C, Arnold RS, Schechner J, Chung J, Mercurio AM, Alani R, Ryu B, Fan CY, Cuezva JM, Martinez M, Arbiser JL (2005) Malignant transformation of human cells by constitutive expression of platelet-derived growth factor-BB. J Biol Chem 280:13936–13943PubMedCrossRefGoogle Scholar
  26. 26.
    Govindarajan B, Sligh JE, Vincent BJ, Li M, Canter JA, Nickoloff BJ, Rodenburg RJ, Smeitink JA, Oberley L, Zhang Y, Slingerland J, Arnold RS, Lambeth JD, Cohen C, Hilenski L, Griendling K, Martinez-Diez M, Cuezva JM, Arbiser JL (2007) Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest 117:719–729PubMedCrossRefGoogle Scholar
  27. 27.
    Hanselmann C, Mauch C, Werner S (2001) Haem oxygenase-1: a novel player in cutaneous wound repair and psoriasis? Biochem J 353:459–466PubMedCrossRefGoogle Scholar
  28. 28.
    Klangby U, Okan I, Magnusson KP, Wendland M, Lind P, Wiman KG (1998) p16/INK4a and p15/INK4b gene methylation and absence of p16/INK4a mRNA and protein expression in Burkitt’s lymphoma. Blood 91:1680–1687PubMedGoogle Scholar
  29. 29.
    Lambeth JD, Kawahara T, Diebold B (2007) Regulation of Nox and Duox enzymatic activity and expression. Free Radic Biol Med 43:319–331PubMedCrossRefGoogle Scholar
  30. 30.
    LaMontagne KR Jr, Moses MA, Wiederschain D, Mahajan S, Holden J, Ghazizadeh H, Frank DA, Arbiser JL (2000) Inhibition of MAP kinase kinase causes morphological reversion and dissociation between soft agar growth and in vivo tumorigenesis in angiosarcoma cells. Am J Pathol 157:1937–1945PubMedCrossRefGoogle Scholar
  31. 31.
    Lapidoth M, Ben-Amitai D, Bhandarkar S, Fried L, Arbiser JL (2009) Efficacy of topical application of eosin for ulcerated hemangiomas. J Am Acad Dermatol 60:350–351PubMedCrossRefGoogle Scholar
  32. 32.
    Lawley LP, Cerimele F, Weiss SW, North P, Cohen C, Kozakewich HP, Mulliken JB, Arbiser JL (2005) Expression of Wilms tumor 1 gene distinguishes vascular malformations from proliferative endothelial lesions. Arch Dermatol 141:1297–1300PubMedCrossRefGoogle Scholar
  33. 33.
    Leaute-Labreze C, de la Dumas RE, Hubiche T, Boralevi F, Thambo JB, Taieb A (2008) Propranolol for severe hemangiomas of infancy. N Engl J Med 358:2649–2651PubMedCrossRefGoogle Scholar
  34. 34.
    Lee HM, Shin DM, Yuk JM, Shi G, Choi DK, Lee SH, Huang SM, Kim JM, Kim CD, Lee JH, Jo EK (2011) Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. J Immunol 186:1248–1258PubMedCrossRefGoogle Scholar
  35. 35.
    Levine SM (1992) The role of reactive oxygen species in the pathogenesis of multiple sclerosis. Med Hypotheses 39:271–274PubMedCrossRefGoogle Scholar
  36. 36.
    Lunec J, Herbert K, Blount S, Griffiths HR, Emery P (1994) 8-Hydroxydeoxyguanosine. A marker of oxidative DNA damage in systemic lupus erythematosus. FEBS Lett 348:131–138PubMedCrossRefGoogle Scholar
  37. 37.
    Maranchie JK, Zhan Y (2005) Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res 65:9190–9193PubMedCrossRefGoogle Scholar
  38. 38.
    Mishra MV, Bisht KS, Sun L, Muldoon-Jacobs K, Awwad R, Kaushal A, Nguyen P, Huang L, Pennington JD, Markovina S, Bradbury CM, Gius D (2008) DNMT1 as a molecular target in a multimodality-resistant phenotype in tumor cells. Mol Cancer Res 6:243–249PubMedCrossRefGoogle Scholar
  39. 39.
    Mochizuki T, Furuta S, Mitsushita J, Shang WH, Ito M, Yokoo Y, Yamaura M, Ishizone S, Nakayama J, Konagai A, Hirose K, Kiyosawa K, Kamata T (2006) Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene 25:3699–3707PubMedCrossRefGoogle Scholar
  40. 40.
    Orcutt KP, Parsons AD, Sibenaller ZA, Scarbrough PM, Zhu Y, Sobhakumari A, Wilke WW, Kalen AL, Goswami P, Miller FJ Jr, Spitz DR, Simons AL (2011) Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res 71:3932–3940PubMedCrossRefGoogle Scholar
  41. 41.
    Perry BN, Govindarajan B, Bhandarkar SS, Knaus UG, Valo M, Sturk C, Carrillo CO, Sohn A, Cerimele F, Dumont D, Losken A, Williams J, Brown LF, Tan X, Ioffe E, Yancopoulos GD, Arbiser JL (2006) Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice. J Invest Dermatol 126:2316–2322PubMedCrossRefGoogle Scholar
  42. 42.
    Perry DK, Hand WL, Edmondson DE, Lambeth JD (1992) Role of phospholipase D-derived diradylglycerol in the activation of the human neutrophil respiratory burst oxidase. Inhibition by phosphatidic acid phosphohydrolase inhibitors. J Immunol 149:2749–2758PubMedGoogle Scholar
  43. 43.
    Qiu RG, Chen J, Kirn D, McCormick F, Symons M (1995) An essential role for Rac in Ras transformation. Nature 374:457–459PubMedCrossRefGoogle Scholar
  44. 44.
    Sanz-Cameno P, Martin-Vilchez S, Lara-Pezzi E, Borque MJ, Salmeron J, de Munoz RP, Solis JA, Lopez-Cabrera M, Moreno-Otero R (2006) Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV X protein. Am J Pathol 169:1215–1222PubMedCrossRefGoogle Scholar
  45. 45.
    Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10:2247–2258PubMedGoogle Scholar
  46. 46.
    Shinohara M, Shang WH, Kubodera M, Harada S, Mitsushita J, Kato M, Miyazaki H, Sumimoto H, Kamata T (2007) Nox1 redox signaling mediates oncogenic Ras-induced disruption of stress fibers and focal adhesions by down-regulating Rho. J Biol Chem 282:17640–17648PubMedCrossRefGoogle Scholar
  47. 47.
    Stoff B, Mackelfresh J, Fried L, Cohen C, Arbiser JL (2010) A nonsteroidal alternative to impetiginized eczema in the emergency room. J Am Acad Dermatol 63:537–539PubMedCrossRefGoogle Scholar
  48. 48.
    Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794–798PubMedGoogle Scholar
  49. 49.
    Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA (1994) Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 93:2357–2364PubMedCrossRefGoogle Scholar
  50. 50.
    Torisu-Itakura H, Lee JH, Huynh Y, Ye X, Essner R, Morton DL (2007) Monocyte-derived IL-10 expression predicts prognosis of stage IV melanoma patients. J Immunother 30:831–838PubMedCrossRefGoogle Scholar
  51. 51.
    Trindade F, Tellechea O, Torrelo A, Requena L, Colmenero I (2011) Wilms tumor 1 expression in vascular neoplasms and vascular malformations. Am J Dermatopathol 33(6):569–572PubMedCrossRefGoogle Scholar
  52. 52.
    Verma A, Ihler GM (2002) Activation of Rac, Cdc42 and other downstream signalling molecules by Bartonella bacilliformis during entry into human endothelial cells. Cell Microbiol 4:557–569PubMedCrossRefGoogle Scholar
  53. 53.
    Vicent S, Chen R, Sayles LC, Lin C, Walker RG, Gillespie AK, Subramanian A, Hinkle G, Yang X, Saif S, Root DE, Huff V, Hahn WC, Sweet-Cordero EA (2010) Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. J Clin Invest 120:3940–3952PubMedCrossRefGoogle Scholar
  54. 54.
    Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270PubMedGoogle Scholar
  55. 55.
    Weaver-Feldhaus J, Gruis NA, Neuhausen S, Le PD, Stockert E, Skolnick MH, Kamb A (1994) Localization of a putative tumor suppressor gene by using homozygous deletions in melanomas. Proc Natl Acad Sci USA 91:7563–7567PubMedCrossRefGoogle Scholar
  56. 56.
    Yamaura M, Mitsushita J, Furuta S, Kiniwa Y, Ashida A, Goto Y, Shang WH, Kubodera M, Kato M, Takata M, Saida T, Kamata T (2009) NADPH oxidase 4 contributes to transformation phenotype of melanoma cells by regulating G2-M cell cycle progression. Cancer Res 69:2647–2654PubMedCrossRefGoogle Scholar
  57. 57.
    Yamini B, Yu X, Dolan ME, Wu MH, Kufe DW, Weichselbaum RR (2007) Inhibition of nuclear factor-kappaB activity by temozolomide involves O6-methylguanine induced inhibition of p65 DNA binding. Cancer Res 67:6889–6898PubMedCrossRefGoogle Scholar
  58. 58.
    Zietz C, Rossle M, Haas C, Sendelhofert A, Hirschmann A, Sturzl M, Lohrs U (1998) MDM-2 oncoprotein overexpression, p53 gene mutation, and VEGF up-regulation in angiosarcomas. Am J Pathol 153:1425–1433PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG (outside the USA) 2012

Authors and Affiliations

  1. 1.Department of DermatologyEmory University School of MedicineAtlantaUSA
  2. 2.Atlanta Veterans Administration Medical CenterAtlantaUSA

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