Skip to main content

Advertisement

SpringerLink
Log in

Review on NAD(P)H dehydrogenase quinone 1 (NQO1) pathway

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

NQO1 is an enzyme present in humans which is encoded by NQO1 gene. It is a protective antioxidant agent, versatile cytoprotective agent and regulates the oxidative stresses of chromatin binding proteins for DNA damage in cancer cells. The oxidization of cellular pyridine nucleotides causes structural alterations to NQO1 and changes in its capacity to binding of proteins. A strategy based on NQO1 to have protective effect against cancer was developed by organic components to enhance NQO1 expression. The quinone derivative compounds like mitomycin C, RH1, E09 (Apaziquone) and β-lapachone causes cell death by NQO1 reduction of two electrons. It was also known to be overexpressed in various tumor cells of breast, lung, cervix, pancreas and colon when it was compared with normal cells in humans. The mechanism of NQO1 by the reduction of FAD by NADPH to form FADH2 is by two ways to inhibit cancer cell development such as suppression of carcinogenic metabolic activation and prevention of carcinogen formation. The NQO1 exhibit suppression of chemical-mediated carcinogenesis by various properties of NQO1 which includes, detoxification of quinone scavenger of superoxide anion radical, antioxidant enzyme, protein stabilizer. This review outlines the NQO1 structure, mechanism of action to inhibit the cancer cell, functions of NQO1 against oxidative stress, drugs acting on NQO1 pathways, clinical significance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ACF:

Aberrant crypt foci

AD:

Alzhemier’s disease

AKT:

Serine/threonine-protein kinase

ALDH:

Aldehyde dehydrogenases

AOM:

Azoxymethane

APTS:

3-Aminopropyltrictriethoxysilane

BCL3:

B-cell lymphoma 3-encoded protein

CTAB:

Cetyl trimethyl ammonium bromide

DNA:

Deoxyribonucleic acid

EGFR:

Epidermal growth factor receptor

EGFRv III:

Epidermal growth factor receptor variant III

O9:

(3-Hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione) prop-β-en-ol)

EMT:

Epithelial-to-mesenchymal transition

FAD:

Flavin adenine dinucleotide

GBM:

Glioblastoma multiforme

GST:

Glutathione S transferase

GSTP:

Glutathione S transferase P

HCC:

Hepatocellular carcinoma

HER:

Human epidermal growth factor receptor

HIV:

Human immunodeficiency virus

HL-60:

Human leukemia cell line

HTAB:

Hexadecyl trimethyl ammonium bromide

IHC:

Immunohistochemistry

IL8:

Interleukin 8

IKKa:

Inhibitory-κB kinase

JNK:

C-Jun NH2-terminal kinase

KRAS:

Kirsten rat sarcoma virus

LPC:

Lysophosphatidylcholine

MAPK:

Microtubule associated protein kinases

MS:

Multiple sclerosis

MSNP:

Mesoporous silica nanoparticles

NADPH:

Nicotinamide adenine dinucleotide phosphate

NFB:

Nuclear factor-B

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NOS:

Nitrous oxide

NQO1:

NAD(P)H dehydrogenase quinone 1

NSCLC:

Non-small cell lung cancer

PARP1:

Poly [ADP-ribose] polymerase 1

PD:

Parkinson’s disease

PDA:

Patent ductus arteriosus

PDT:

Photodynamic therapy

PFB:

2-(4-Fluorophenoxy)-5-phenylbenzoic acid

PEG:

Polyethylene glycol

PFB:

Pirfenidone

PINK1:

PTEN-induced kinase 1

PLA:

Polylactic acid

PLP-NPs:

PH/ROS cascade responsive and self-accelerating drug release nanoparticle system

PMRS:

Plasma membrane redox system

PTEN:

Phosphatase and tensin homolog

PTX:

Paclitaxel

qRT-PCR:

Quantifying real time polymerase chain reaction

ROS:

Reactive oxygen species

SCC:

Cutaneous squamous cell carcinoma

SFN:

Small fiber neuropathy

SIRT6:

Sirtuin 6

SMAD:

Sma genes and the Drosophila Mad

SOD:

Superoxide dismutase

TEOS:

Tetraethyl orthosilicate

TGF:

Transforming growth factor

THQ:

Thymohydroquinone

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

TSB:

Transcriptional strand bias

U87MG:

Uppsala 87 malignant glioma

UGT:

Uridine diphosphate-glucuronyltransferase

XIAP:

X-linked inhibitor of apoptosis protein

ZEB1:

Zinc-finger E-box binding protein 1

References

  1. Hassanpour SH, Dehghani M (2017) Review of cancer from perspective of molecular. J Cancer Res Pract 4(4):127–129

    Article  Google Scholar 

  2. Falzone L, Salomone S, Libra M, John D, Lane R (2018) Evolution of cancer pharmacological treatments at the turn of the third millennium. Rev Front Pharmacol 9:1300

    Article  CAS  Google Scholar 

  3. McQuerry JA, Chang JT, Bowtell DDL, Cohen A, Bild AH (2017) Mechanisms and clinical implications of tumor heterogeneity and convergence on recurrent phenotypes. J Mol Med 95(11):1167–1178

    Article  CAS  PubMed  Google Scholar 

  4. Sonnenschein C, Soto AM (2020) Over a century of cancer research: inconvenient truths and promising leads. PLoS Biol 18(4):1–12. https://doi.org/10.1371/journal.pbio.3000670

    Article  CAS  Google Scholar 

  5. Bertolaso M (2016) Cancer biology. In: History, philosophy and theory of the life sciences, vol 18. Springer, Cham, pp 1–16

  6. Silvers MA, Deja S, Singh N, Egnatchik RA, Sudderth J, Luo X et al (2017) The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1 pancreatic cancer cells, causing perturbation in central carbon metabolism. J Biol Chem 292(44):18203–18216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Goracy J, Bogacz A, Uzar I, Wolek M, Łochyńska M, Ziętek P et al (2021) The analysis of NADPH quinone reductase 1 (NQO1) polymorphism in Polish patients with colorectal cancer. Biomolecules 11(7):1–9

    Article  Google Scholar 

  8. Louie TM, Yang H, Karnchanaphanurach P, Sunney Xie X, Xun L (2002) FAD is a preferred substrate and an inhibitor of Escherichia coli general NAD(P)H:flavin oxidoreductase. J Biol Chem 277(42):39450–39455. https://doi.org/10.1074/jbc.M206339200

    Article  CAS  PubMed  Google Scholar 

  9. Ernster L (1958) Diaphorase activities in liver cytoplasmic fractions. Fed Proc 17(1):216

    Google Scholar 

  10. Maerki F, Martius C (1961) Vitamin K reductase, from cattle and ratliver. Biochem Z 334:293–303

    CAS  PubMed  Google Scholar 

  11. Ross D, Siegel D (2017) Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Front Physiol 8:595

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ross D, Siegel D (2021) The diverse functionality of NQO1 and its roles in redox control. Redox Biol 41:101950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Castello A, Castello A, Fischer B, Fischer B, Eichelbaum K, Eichelbaum K et al (2012) Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149(6):1393–1406

    Article  CAS  PubMed  Google Scholar 

  14. Bianchet MA, Faig M, Amzel LM (2004) Structure and mechanism of NAD[P]H:quinone acceptor oxidoreductases (NQO). Methods Enzymol 382:144–174

    Article  CAS  PubMed  Google Scholar 

  15. Zhang K, Chen D, Ma K, Wu X, Hao H, Jiang S (2018) NAD(P)H:quinone oxidoreductase 1 (NQO1) as a therapeutic and diagnostic target in cancer. J Med Chem 61(16):6983–7003

    Article  CAS  PubMed  Google Scholar 

  16. Karadagi A, Cavedon AG, Zemack H, Nowak G, Eybye ME, Zhu X et al (2020) Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency. Sci Rep 10(1):1–11

    Article  Google Scholar 

  17. Medina-Carmona E, Neira JL, Salido E, Fuchs JE, Palomino-Morales R, Timson DJ et al (2017) Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism. Sci Rep 7:44532. https://doi.org/10.1038/srep44532

  18. Ross D, Siegel D (2017) Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Front Physiol 8:595. https://doi.org/10.3389/fphys.2017.00595

  19. Blaza JN, Bridges HR, Aragão D, Dunn EA, Heikal A, Cook GM et al (2017) The mechanism of catalysis by type-II NADH:quinone oxidoreductases. Sci Rep 7:1–12. https://doi.org/10.1038/srep40165

    Article  CAS  Google Scholar 

  20. Mohammed SJ, Salih AK, Rashid MAM, Omer KM, Abdalkarim KA (2020) Synthesis, spectroscopic studies and keto-enol tautomerism of novel 1,3,4-thiadiazole derivative containing 3-mercaptobutan-2-one and quinazolin-4-one moieties. Molecules 25(22):5441

    Article  CAS  PubMed Central  Google Scholar 

  21. Hassani M, Cai W, Holley DC, Lineswala JP, Maharjan BR, Ebrahimian GR et al (2005) Novel lavendamycin analogues as antitumor agents: Synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1. J Med Chem 48(24):7733–7749

    Article  CAS  PubMed  Google Scholar 

  22. Li R, Bianchet MA, Talalay P, Amzel LM (1995) The three-dimensional structure of NAD(P)H:quinone reductase a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. Proc Natl Acad Sci USA 92(19):8846–8850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Faig M (2000) Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release. Proc Natl Acad Sci USA 97(7):3177–3182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Saito K, Rutherford AW, Ishikita H (2013) Mechanism of proton-coupled quinone reduction in Photosystem II. Proc Natl Acad Sci USA 110(3):954–959

    Article  CAS  PubMed  Google Scholar 

  25. Roche J, Groenen-Serrano K, Reynes O, Chauvet F, Tzedakis T (2014) NADH regenerated using immobilized FDH in a continuously supplied reactor—application to L-lactate synthesis. Chem Eng J 239:216–225

    Article  CAS  Google Scholar 

  26. Tedeschi G, Chen S, Massey V (1995) DT-diaphorase: redox potential, steady-state, and rapid reaction studies. J Biol Chem 270(3):1198–1204

    Article  CAS  PubMed  Google Scholar 

  27. Hosoda S, Nakamura W, Hayashi K (1974) Properties and reaction mechanism of DT diaphorase from rat liver. J Biol Chem 249(20):6416–6423

    Article  CAS  PubMed  Google Scholar 

  28. Kwiek JJ, Haystead TAJ, Rudolph J (2004) Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines. Biochemistry 43(15):4538–4547

    Article  CAS  PubMed  Google Scholar 

  29. Verma R, Mitchell-Koch K (2017) In silico studies of small molecule interactions with enzymes reveal aspects of catalytic function. Catalysts 7(7):212

    Article  PubMed  PubMed Central  Google Scholar 

  30. Beaver SK, Mesa-Torres N, Pey AL, Timson DJ (2019) NQO1: A target for the treatment of cancer and neurological diseases, and a model to understand loss of function disease mechanisms. Biochim Biophys Acta Proteins Proteomics 1867(7–8):663–676. https://doi.org/10.1016/j.bbapap.2019.05.002

    Article  CAS  PubMed  Google Scholar 

  31. Iskander K, Gaikwad A, Paquet M, Long DJ, Brayton C, Barrios R et al (2005) Lower induction of p53 and decreased apoptosis in NQO1-null mice lead to increased sensitivity to chemical-induced skin carcinogenesis. Cancer Res 65(6):2054–2058

    Article  CAS  PubMed  Google Scholar 

  32. Asher G, Bercovich Z, Tsvetkov P, Shaul Y, Kahana C (2005) 20S proteasomal degradation of ornithine decarboxylase is regulated by NQO1. Mol Cell 17(5):645–655

    Article  CAS  PubMed  Google Scholar 

  33. Asher G, Lotem J, Cohen B, Sachs L, Shaul Y (2001) Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci USA 98(3):1188–1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Timofeev KN (2004) Role of NAD(P)H: quinone oxidoreductase encoded by drgA gene in reduction of exogenous quinones in Cyanobacterium synechocystis sp. PCC 6803 Cells. Biochemistry 69(2):137–142

    PubMed  Google Scholar 

  35. Oh E, Kim J, Kim JM, Kim SJ, Lee J, Hong S et al (2016) NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 7:1–14. https://doi.org/10.1038/ncomms13593

    Article  CAS  Google Scholar 

  36. Ben-Nissan G, Sharon M (2014) Regulating the 20S proteasome ubiquitin-independent degradation pathway. Biomolecules 4(3):862–884

    Article  PubMed  PubMed Central  Google Scholar 

  37. Moscovitz O, Tsvetkov P, Hazan N, Michaelevski I, Keisar H, Ben-Nissan G et al (2012) A mutually inhibitory feedback loop between the 20S proteasome and its regulator, NQO1. Mol Cell 47(1):76–86. https://doi.org/10.1016/j.molcel.2012.05.049

    Article  CAS  PubMed  Google Scholar 

  38. Vasiliou V, Ross D, Nebert DW (2006) Update of the NAD(P)H: quinone oxidoreductase (NQO) gene family. Hum Genomics 2(5):329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roviello G, D’Angelo A, Sirico M, Pittacolo M, Conter FU, Sobhani N (2021) Advances in anti-BRAF therapies for lung cancer. Invest New Drugs 39(3):879–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tsvetkov P, Asher G, Reiss V, Shaul Y, Sachs L, Lotem J (2005) Inhibition of NAD(P)H: quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin. Proc Natl Acad Sci USA 102(15):5535–5540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Laplante G, Zhang W (2021) Targeting the ubiquitin-proteasome system for cancer therapeutics by small-molecule inhibitors. Cancers (Basel) 13(12):1–43

    Article  Google Scholar 

  42. Adamovich Y, Shlomai A, Tsvetkov P, Umansky KB, Reuven N, Estall JL et al (2013) The protein level of PGC-1α, a key metabolic regulator, is controlled by NADH-NQO1. Mol Cell Biol 33(13):2603–2613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hwang JH, Kim DW, Jo EJ, Kim YK, Jo YS, Park JH et al (2009) Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice. Diabetes 58(4):965–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kostecka A, Sznarkowska A, Meller K, Acedo P, Shi Y, Sakil HAM et al (2014) JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress. Cell Death Dis 5(10):e1484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Karaca E, Haliloglu T, Nussinov R (2008) Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis. Nucleic Acids Res 36(15):5033–5049

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gong J, Costanzo A, Yang H, Melino G, Kaelin WG, Levrero M et al (1999) The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399(6738):806–809

    Article  CAS  PubMed  Google Scholar 

  47. Alard A, Fabre B, Anesia R, Marboeuf C, Pierre P, Susini C et al (2010) NAD(P)H quinone-oxydoreductase 1 protects eukaryotic translation initiation factor 4gi from degradation by the proteasome. Mol Cell Biol 30(4):1097–1105

    Article  PubMed  Google Scholar 

  48. Chesis PL, Levin DE, Smith MT, Ernster L, Ames BN (1984) Mutagenicity of quinones: Pathways of metabolic activation and detoxification. Proc Natl Acad Sci USA 81(6I):1696–1700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lind C, Hochstein P, Ernster L (1982) DT-diaphorase as a quinone reductase: a cellular control device against semiquinone and superoxide radical formation. Arch Biochem Biophys 216(1):178–185

    Article  CAS  PubMed  Google Scholar 

  50. Thor H, Smith MT, Hartzell P, Bellomo G, Jewell SA, Orrenius S (1982) The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes A study of the implications of oxidative stress in intact cells. J Biol Chem 257(20):12419–12425

    Article  CAS  PubMed  Google Scholar 

  51. Thomas DJ, Sadler A, Subrahmanyam VV, Siegel D, Reasor MJ, Wierda D et al (1990) Bone marrow stromal cell bioactivation and detoxification of the benzene metabolite hydroquinone: Comparison of macrophages and fibroblastoid cells. Mol Pharmacol 37(2):255–262

    CAS  PubMed  Google Scholar 

  52. Wefers H, Sies H (1983) Hepatic low-level chemiluminescence during redox cycling of menadione and the menadione-glutathione conjugate: relation to glutathione and NAD(P)H:quinone reductase (DT-diaphorase) activity. Arch Biochem Biophys 224(2):568–578

    Article  CAS  PubMed  Google Scholar 

  53. Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ et al (2004) NAD(P)H:quinone oxidoreductase 1: Role as a superoxide scavenger. Mol Pharmacol 65(5):1238–1247

    Article  CAS  PubMed  Google Scholar 

  54. Beyer RE, Segura-Aguilar J, Di Bernardo S, Cavazzoni M, Fato R, Fiorentini D et al (1996) The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Proc Natl Acad Sci USA 93(6):2528–2532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chan K, Han XD, Kan YW (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci USA 98(8):4611–4616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Talalay P (2000) Chemoprotection against cancer by induction of Phase 2 enzymes. BioFactors 12(1–4):5–11

    Article  CAS  PubMed  Google Scholar 

  57. Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116

    Article  CAS  PubMed  Google Scholar 

  58. Holtzclaw WD, Dinkova-Kostova AT, Talalay P (2004) Protection against electrophile and oxidative stress by induction of phase 2 genes: the quest for the elusive sensor that responds to inducers. Adv Enzyme Regul 44(1):335–367

    Article  CAS  PubMed  Google Scholar 

  59. Dinkova-Kostova AT, Holtzclaw WD, Kensler TW (2005) The role of Keap1 in cellular protective responses. Chem Res Toxicol 18(12):1779–1791

    Article  CAS  PubMed  Google Scholar 

  60. Lakin ND, Jackson SP (1999) Regulation of p53 in response to DNA damage. Oncogene 18(53):7644–7655

    Article  CAS  PubMed  Google Scholar 

  61. Lavin MF, Gueven N (2006) The complexity of p53 stabilization and activation. Cell Death Differ 13(6):941–950

    Article  CAS  PubMed  Google Scholar 

  62. Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y (2006) The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry 45(20):6372–6378

    Article  CAS  PubMed  Google Scholar 

  63. Pey AL, Megarity CF, Timson DJ (2019) NAD(P)H quinone oxidoreductase (NQO1): An enzyme which needs just enough mobility, in just the right places. Biosci Rep. https://doi.org/10.1042/BSR20180459

  64. Siegel D, Yan C, Ross D (2012) NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83(8):1033–1040

    Article  CAS  PubMed  Google Scholar 

  65. Stiborová M, Indra R, Moserová M, Frei E, Schmeiser HH, Kopka K et al (2016) NADH: cytochrome b5 reductase and cytochrome b5 can act as sole electron donors to human cytochrome P450 1A1-mediated oxidation and DNA adduct formation by benzo[a]pyrene. Chem Res Toxicol 29(8):1325–1334

    Article  PubMed  PubMed Central  Google Scholar 

  66. Iyanagi T, Yamazaki I (1970) Difference in the mechanism of quinone reduction by the Nadh dehydrogenase and the Nad(P)H dehydrogenase (Dt-diaphorase). Biochim Biophys Acta 216:282–294

    Article  CAS  PubMed  Google Scholar 

  67. Iskander K, Li J, Han S, Zheng B, Jaiswal AK (2017) NQO1 and NQO2 regulation of humoral immunity and autoimmunity. J Biol Chem 292(5):2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gayam SR, Venkatesan P, Sung YM, Sung SY, Hu SH, Hsu HY et al (2016) An NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery: In vitro and in vivo. Nanoscale 8(24):12307–12317

    Article  CAS  PubMed  Google Scholar 

  69. Mamaeva V, Sahlgren C, Lindén M (2013) Mesoporous silica nanoparticles in medicine—recent advances. Adv Drug Deliv Rev 65(5):689–702

    Article  CAS  PubMed  Google Scholar 

  70. Tarn D, Ashley CE, Xue M, Carnes EC, Zink JI, Brinker CJ (2013) Mesoporous silica nanoparticle nanocarriers: biofunctionality and biocompatibility. Acc Chem Res 46(3):792–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vivero-Escoto JL, Slowing II, Lin VSY, Trewyn BG (2010) Mesoporous silica nanoparticles for intracellular controlled drug delivery. Small 6(18):1952–1967

    Article  CAS  PubMed  Google Scholar 

  72. Panyam J, Labhasetwar V (2003) Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 55(3):329–347

    Article  CAS  PubMed  Google Scholar 

  73. Blanco E, Bey EA, Dong Y, Weinberg BD, Sutton DM, Boothman DA et al (2007) β-Lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. J Control Release 122(3):365–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pink JJ, Planchon SM, Tagliarino C, Varnes ME, Siegel D, Boothman DA (2000) NAD(P)H:quinone oxidoreductase activity is the principal determinant of β-lapachone cytotoxicity. J Biol Chem 275(8):5416–5424

    Article  CAS  PubMed  Google Scholar 

  75. Reinicke KE, Bey EA, Bentle MS, Pink JJ, Ingalls ST, Hoppel CL et al (2005) Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Clin Cancer Res 11(8):3055–3064

    Article  CAS  PubMed  Google Scholar 

  76. Volpato M, Abou-Zeid N, Tanner RW, Glassbrook LT, Taylor J, Stratford I et al (2007) Chemical synthesis and biological evaluation of a NAD(P)H:quinone oxidoreductase-1-targeted tripartite quinone drug delivery system. Mol Cancer Ther 6(12):3122–3130

    Article  CAS  PubMed  Google Scholar 

  77. Phillips RM, Jaffar M, Maitland DJ, Loadman PM, Shnyder SD, Steans G et al (2004) Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs. Biochem Pharmacol 68(11):2107–2116

    Article  CAS  PubMed  Google Scholar 

  78. Wang H, Gao Z, Liu X, Agarwal P, Zhao S, Conroy DW et al (2018) Targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance. Nat Commun 9(1):562

    Article  PubMed  PubMed Central  Google Scholar 

  79. Cheng ST, Hu JL, Ren JH, Yu HB, Zhong S, Wai Wong VK et al (2021) Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx. J Hepatol 74(3):522–534

    Article  CAS  PubMed  Google Scholar 

  80. De Grey ADNJ (2005) The plasma membrane redox system: A candidate source of aging-related oxidative stress. Age (Omaha) 27(2):129–138

    Article  Google Scholar 

  81. Zhu H, Jia Z, Mahaney JE, Ross D, Misra HP, Trush MA et al (2007) The highly expressed and inducible endogenous NAD(P)H:quinone oxidoreductase 1 in cardiovascular cells acts as a potential superoxide scavenger. Cardiovasc Toxicol 7(3):202–211

    Article  CAS  PubMed  Google Scholar 

  82. Siegel D, Franklin WA, Ross D (1998) Immunohistochemical detection of NAD(P)H: quinone oxidoreductase in human lung and lung tumors. Clin Cancer Res 4(9):2065–2070

    CAS  PubMed  Google Scholar 

  83. Garate M, Wani AA, Li G (2010) The NAD(P)H: Quinone Oxidoreductase 1 induces cell cycle progression and proliferation of melanoma cells. Free Radic Biol Med 48(12):1601–1609. https://doi.org/10.1016/j.freeradbiomed.2010.03.003

    Article  CAS  PubMed  Google Scholar 

  84. Nioi P, Hayes JD (2004) Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res Fundam Mol Mech Mutagen 555(1–2):149–171

    Article  CAS  Google Scholar 

  85. Lee W-S, Ham W, Kim J (2021) Roles of NAD(P)H:quinone oxidoreductase 1 in diverse diseases. Life 11(12):1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Awadallah NS, Dehn D, Shah RJ, Russell Nash S, Chen YK, Ross D et al (2008) NQO1 expression in pancreatic cancer and its potential use as a biomarker. Appl Immunohistochem Mol Morphol 16(1):24–31

    Article  CAS  PubMed  Google Scholar 

  87. Lewis AM, Ough M, Hinkhouse MM, Tsao MS, Oberley LW, Cullen JJ (2005) Targeting NAD(P)H:quinone oxidoreductase (NQO1) in pancreatic cancer. Mol Carcinog 43(4):215–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li Z, Zhang Y, Jin T, Men J, Lin Z, Qi P et al (2015) NQO1 protein expression predicts poor prognosis of non-small cell lung cancers. BMC Cancer 15(1):1–9

    Google Scholar 

  89. Denicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K et al (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475(7354):106–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li L, Dong H, Song E, Xu X, Liu L, Song Y (2014) Nrf2/ARE pathway activation, HO-1 and NQO1 induction by polychlorinated biphenyl quinone is associated with reactive oxygen species and PI3K/AKT signaling. Chem Biol Interact 209(1):56–67. https://doi.org/10.1016/j.cbi.2013.12.005

    Article  CAS  PubMed  Google Scholar 

  91. Madajewski B, Boatman MA, Chakrabarti G, Boothman DA, Bey EA (2016) Depleting tumor-NQO1 potentiates anoikis and inhibits growth of NSCLC. Mol Cancer Res 14(1):14–25

    Article  CAS  PubMed  Google Scholar 

  92. Leinonen HM, Kansanen E, Pölönen P, Heinäniemi M, Levonen AL (2014) Role of the keap1-Nrf2 pathway in cancer. Adv Cancer Res 122:281–320

    Article  CAS  PubMed  Google Scholar 

  93. Leinonen HM, Kansanen E, Pölönen P, Heinäniemi M, Levonen AL (2015) Dysregulation of the Keap1-Nrf2 pathway in cancer. Biochem Soc Trans 43:645–649

    Article  CAS  PubMed  Google Scholar 

  94. Zhang L, Liu Q, Huang L, Yang F, Liu A, Zhang J (2020) Combination of lapatinib and luteolin enhances the therapeutic efficacy of lapatinib on human breast cancer through the FOXO3a/NQO1 pathway. Biochem Biophys Res Commun 531(3):364–371. https://doi.org/10.1016/j.bbrc.2020.07.049

    Article  CAS  PubMed  Google Scholar 

  95. Buranrat B, Chau-In S, Prawan A, Puapairoj A, Zeekpudsa P, Kukongviriyapan V (2012) NQO1 expression correlates with Cholangiocarcinoma prognosis. Asian Pacific J Cancer Prev. 13(Suppl. 1):131–136

    Google Scholar 

  96. Chisla S, Massey V (1989) Mechanisms of flavoprotein-catalyzed reactions. Eur J Biochem 181(1):1–17

    Article  Google Scholar 

  97. Cui X, Li L, Yan G, Meng K, Lin Z, Nan Y et al (2015) High expression of NQO1 is associated with poor prognosis in serous ovarian carcinoma. BMC Cancer 15(1):244

    Article  PubMed  PubMed Central  Google Scholar 

  98. Ma Y, Kong J, Yan G, Ren X, Jin D, Jin T et al (2014) NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 14(1):414

    Article  PubMed  PubMed Central  Google Scholar 

  99. Lyn-Cook BD, Yan-Sanders Y, Moore S, Taylor S, Word B, Hammons GJ (2006) Increased levels of NAD(P)H: quinone oxidoreductase 1 (NQO1) in pancreatic tissues from smokers and pancreatic adenocarcinomas: a potential biomarker of early damage in the pancreas. Cell Biol Toxicol 22(2):73–80

    Article  CAS  PubMed  Google Scholar 

  100. Thapa D, Huang SB, Muñoz AR, Yang X, Bedolla RG, Hung CN et al (2020) Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling. Commun Biol 3(1):1–12. https://doi.org/10.1038/s42003-019-0720-z

    Article  CAS  Google Scholar 

  101. Izumi K, Li Y, Zheng Y, Gordetsky J, Yao JL, Miyamoto H (2012) Seminal plasma proteins in prostatic carcinoma: increased nuclear semenogelin I expression is a predictor of biochemical recurrence after radical prostatectomy. Hum Pathol 43(11):1991–2000

    Article  CAS  PubMed  Google Scholar 

  102. Chandran UR, Ma C, Dhir R, Bisceglia M, Lyons-Weiler M, Liang W et al (2007) Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer 7:e7899

    Article  Google Scholar 

  103. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al (2012) The mutational landscape of lethal castration-resistant prostate cancer. Nature 487(7406):239–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zawel L, Le Dai J, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B et al (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1(4):611–617

    Article  CAS  PubMed  Google Scholar 

  105. Goswami CP, Nakshatri H (2014) PROGgeneV2: enhancements on the existing database. BMC Cancer 14(1):970

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lamberti MJ, Morales Vasconsuelo AB, Chiaramello M, Ferreira VF, Macedo Oliveira M, Baptista Ferreira S et al (2018) NQO1 induction mediated by photodynamic therapy synergizes with β-Lapachone-halogenated derivative against melanoma. Biomed Pharmacother 108(September):1553–1564

    Article  CAS  PubMed  Google Scholar 

  107. Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO et al (2011) Photodynamic therapy of cancer: an update. CA Cancer J Clin 61(4):250–281

    Article  PubMed  PubMed Central  Google Scholar 

  108. Huang Y-Y, Vecchio D, Avci P, Yin R, Garcia-Diaz M, Hamblin MR (2014) Melanoma resistance to photodynamic therapy: new insights. Biol Chem 394(2):239–250

    Article  Google Scholar 

  109. Boothman DA, Pardee AB (1989) Inhibition of radiation-induced neoplastic transformation by β-lapachone. Proc Natl Acad Sci USA 86(13):4963–4967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dunna NR, Anuradha C, Vure S, Sailaja K, Surekha D, Raghunadharao D et al (2011) NQO1*2 [NAD(P)H: Quinone oxidoreductase 1] polymorphism and its influence on acute leukemia risk. Biol Med 3(3):19–25

    CAS  Google Scholar 

  111. Wu JM, Oraee A, Doonan BB, Pinto JT, Hsieh T-C (2016) Activation of NQO1 in NQO1*2 polymorphic human leukemic HL-60 cells by diet-derived sulforaphane. Exp Hematol Oncol 5(1):27

    Article  PubMed  PubMed Central  Google Scholar 

  112. Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ et al (2007) Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomarkers Prev 16(4):847–851

    Article  CAS  PubMed  Google Scholar 

  113. Guo S, Cheng X, Lim JH, Liu Y, Kao HY (2014) Control of antioxidative response by the tumor suppressor protein PML through regulating Nrf2 activity. Mol Biol Cell 25(16):2485–2498

    Article  PubMed  PubMed Central  Google Scholar 

  114. Zhang QL, Li XM, De LD, Zhu MJ, Yim SH, Lee JH et al (2019) Tumor suppressive function of NQO1 in cutaneous squamous cell carcinoma (SCC) cells. Biomed Res Int. https://doi.org/10.1155/2019/2076579

    Article  PubMed  PubMed Central  Google Scholar 

  115. Kallini JR, Hamed N, Khachemoune A (2015) Squamous cell carcinoma of the skin: epidemiology, classification, management, and novel trends. Int J Dermatol 54(2):130–140

    Article  PubMed  Google Scholar 

  116. Riley RJ, Workman P (1992) DT-diaphorase and cancer chemotherapy. Biochem Pharmacol 43(8):1657–1669

    Article  CAS  PubMed  Google Scholar 

  117. Zhong B, Yu J, Hou Y, Ai N, Ge W, Lu JJ et al (2021) A novel strategy for glioblastoma treatment by induction of noptosis, an NQO1-dependent necrosis. Free Radic Biol Med 166(February):104–115. https://doi.org/10.1016/j.freeradbiomed.2021.02.014

    Article  CAS  PubMed  Google Scholar 

  118. Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A et al (2018) Glioblastoma and chemoresistance to alkylating agents: involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 184:13–41

    Article  CAS  PubMed  Google Scholar 

  119. Luo S, Lei K, Xiang D, Ye K (2018) NQO1 is regulated by PTEN in glioblastoma, mediating cell proliferation and oxidative stress. Oxid Med Cell Longev. https://doi.org/10.1155/2018/9146528

    Article  PubMed  PubMed Central  Google Scholar 

  120. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353(19):2012–2024

    Article  CAS  PubMed  Google Scholar 

  121. Kwon J, Lee SR, Yang KS, Ahn Y, Kim YJ, Stadtman ER et al (2004) Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci USA 101(47):16419–16424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhou HZ, Zeng HQ, Yuan D, Ren JH, Cheng ST, Yu HB et al (2019) NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma. Cell Commun Signal 17(1):1–13

    Article  Google Scholar 

  123. Lin L, Sun J, Tan Y, Li Z, Kong F, Shen Y et al (2017) Prognostic implication of NQO1 overexpression in hepatocellular carcinoma. Hum Pathol 69:31–37. https://doi.org/10.1016/j.humpath.2017.09.002

    Article  CAS  PubMed  Google Scholar 

  124. Ran LK, Chen Y, Zhang ZZ, Tao NN, Ren JH, Zhou L et al (2016) SIRT6 overexpression potentiates apoptosis evasion in hepatocellular carcinoma via BCL2-associated X protein-dependent apoptotic pathway. Clin Cancer Res 22(13):3372–3382

    Article  CAS  PubMed  Google Scholar 

  125. Vitiello M, Zullo A, Servillo L, Mancini FP, Borriello A, Giovane A et al (2017) Multiple pathways of SIRT6 at the crossroads in the control of longevity, cancer, and cardiovascular diseases. Ageing Res Rev 35:301–311

    Article  CAS  PubMed  Google Scholar 

  126. Kelloff GJ, Katiwalla M, Reddy BS (1993) Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats. Cancer Res 53(11):2502–2506

    PubMed  Google Scholar 

  127. Smith T, Musk SRR, Johnson IT (1996) Allyl isothiocyanate selectively kills undifferentiated HT29 cells in vitro and suppresses aberrant crypt foci in the colonie mucosa of rats. Biochem Soc Trans 24(3):381S

    Article  CAS  PubMed  Google Scholar 

  128. Begleiter A, Sivananthan K, Curphey TJ, Bird RP (2003) Induction of NAD(P)H quinone: oxidoreductase l inhibits carcinogen-induced aberrant crypt foci in colons of Sprague–Dawley rats. Cancer Epidemiol Biomarkers Prev 12(6):566–572

    CAS  PubMed  Google Scholar 

  129. da Rocha BT, Coser J, Wolf JM, Cardinal BKM, Grivicich I, Simon D et al (2018) Polymorphism located in the upstream region of the RPS19 gene (rs2305809) is associated with cervical cancer: a case-control study. J Cancer Prev 23(3):147–152

    Article  Google Scholar 

  130. Murphy TH, So AP, Vincent SR (1998) Histochemical detection of quinone reductase activity in situ using LY 83583 reduction and oxidation. J Neurochem 70(5):2156–2164

    Article  CAS  PubMed  Google Scholar 

  131. Stringer JL, Gaikwad A, Gonzales BN, Long DJ, Marks LM, Jaiswal AK (2004) Presence and Induction of the enzyme NAD(P)H: quinone oxidoreductase 1 in the central nervous system. J Comp Neurol 471(3):289–297

    Article  CAS  PubMed  Google Scholar 

  132. Van Muiswinkel FL, De Vos RAI, Bol JGJM, Andringa G, Jansen Steur ENH, Ross D et al (2004) Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol Aging 25(9):1253–1262

    Article  PubMed  Google Scholar 

  133. Okada S, Farin FM, Stapleton P, Viernes H, Quigley SD, Powers KM et al (2005) No associations between Parkinson’s disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes. Neurosci Lett 375(3):178–180

    Article  CAS  PubMed  Google Scholar 

  134. Stavropoulou C, Zachaki S, Alexoudi A, Chatzi I, Georgakakos VN, Terzoudi GI et al (2011) The C609T inborn polymorphism in NAD(P)H: quinone oxidoreductase 1 is associated with susceptibility to multiple sclerosis and affects the risk of development of the primary progressive form of the disease. Free Radic Biol Med 51(3):713–718

    Article  CAS  PubMed  Google Scholar 

  135. Agúndez JAG, García-Martín E, Martínez C, Benito-León J, Millán-Pascual J, Calleja P et al (2014) NQO1 gene rs1800566 variant is not associated with risk for multiple sclerosis. BMC Neurol 14(1):87

    Article  PubMed  PubMed Central  Google Scholar 

  136. Butterfield DA, Sultana R (2008) Redox proteomics: Understanding oxidative stress in the progression of age-related neurodegenerative disorders. Expert Rev Proteomics 5(2):157–160

    Article  CAS  PubMed  Google Scholar 

  137. Ma Q, Yang J, Shao M, Dong X, Chen B (2003) Association between NAD(P)H: quinone oxidoreductase and apolipoprotein E gene polymorphisms in Alzheimer’s disease. Zhonghua Yi Xue Za Zhi 83(24):2124–2127

    CAS  PubMed  Google Scholar 

  138. SantaCruz KS, Yazlovitskaya E, Collins J, Johnson J, DeCarli C (2004) Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer’s disease. Neurobiol Aging 25(1):63–69

    Article  CAS  PubMed  Google Scholar 

  139. Smythies JR (1997) Oxidative reactions and schizophrenia: a review-discussion. Schizophr Res 24(3):357–364

    Article  CAS  PubMed  Google Scholar 

  140. Pae CU, Yu HS, Kim JJ, Lee CU, Lee SJ, Jun TY et al (2004) Quinone oxidoreductase (NQO1) gene polymorphism (609C/T) may be associated with tardive dyskinesia, but not with the development of schizophrenia. Int J Neuropsychopharmacol 7(4):495–500

    Article  CAS  PubMed  Google Scholar 

  141. Liou YJ, Wang YC, Lin CC, Bai YM, Lai IC, Liao DL et al (2005) Association analysis of NAD(P)H:quinone oxidoreductase (NQO1) Pro187Ser genetic polymorphism and tardive dyskinesia in patients with schizophrenia in Taiwan [1]. Int J Neuropsychopharmacol 8(3):483–486

    Article  CAS  PubMed  Google Scholar 

  142. Mendez-David I, Tritschler L, El Ali Z, Damiens MH, Pallardy M, David DJ et al (2015) Nrf2-signaling and BDNF: a new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression. Neurosci Lett 597:121–126

    Article  CAS  PubMed  Google Scholar 

  143. Maes M (2008) The cytokine hypothesis of depression: Inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuroendocrinol Lett 29(3):287–291

    CAS  PubMed  Google Scholar 

  144. Türkanoğlu Özçelik A, Can Demirdöğen B, Demirkaya Ş, Adalı O (2017) Association of cytochrome P4502E1 and NAD(P)H:quinone oxidoreductase 1 genetic polymorphisms with susceptibility to large artery atherosclerotic ischemic stroke: a case–control study in the Turkish population. Neurol Sci 38(6):1077–1085

    Article  PubMed  Google Scholar 

  145. Shyu HY, Fong CS, Fu YP, Shieh JC, Yin JH, Chang CY et al (2010) Genotype polymorphisms of GGCX, NQO1, and VKORC1 genes associated with risk susceptibility in patients with large-artery atherosclerotic stroke. Clin Chim Acta 411(11–12):840–845

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The authors have not disclosed any funding.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570015, India

    S. Preethi, K. Arthiga, Amit B. Patil, Asha Spandana & Vikas Jain

Authors
  1. S. Preethi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Arthiga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amit B. Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asha Spandana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vikas Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vikas Jain.

Ethics declarations

Conflict of interest

The authors declared that they have no conflict of interest of this work. The author is responsible for content and the writing the paper.

Ethical approval

Not applicable as it is a review article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Preethi, S., Arthiga, K., Patil, A.B. et al. Review on NAD(P)H dehydrogenase quinone 1 (NQO1) pathway. Mol Biol Rep 49, 8907–8924 (2022). https://doi.org/10.1007/s11033-022-07369-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-07369-2

Keywords

Search

Navigation