Browse > Article
http://dx.doi.org/10.5483/BMBRep.2015.48.11.190

Implications of NQO1 in cancer therapy  

Oh, Eun-Taex (Department of Biomedical Sciences, Inha University)
Park, Heon Joo (Hypoxia-related Disease Research Center, Inha University)
Publication Information
BMB Reports / v.48, no.11, 2015 , pp. 609-617 More about this Journal
Abstract
NAD(P)H:quinone oxidoreductase (NQO1), an obligatory two-electron reductase, is a ubiquitous cytosolic enzyme that catalyzes the reduction of quinone substrates. The NQO1- mediated two-electron reduction of quinones can be either chemoprotection/detoxification or a chemotherapeutic response, depending on the target quinones. When toxic quinones are reduced by NQO1, they are conjugated with glutathione or glucuronic acid and excreted from the cells. Based on this protective effect of NQO1, the use of dietary compounds to induce the expression of NQO1 has emerged as a promising strategy for cancer prevention. On the other hand, NQO1-mediated two-electron reduction converts certain quinone compounds (such as mitomycin C, E09, RH1 and β-lapachone) to cytotoxic agents, leading to cell death. It has been known that NQO1 is expressed at high levels in numerous human cancers, including breast, colon, cervix, lung, and pancreas, as compared with normal tissues. This implies that tumors can be preferentially damaged relative to normal tissue by cytotoxic quinone drugs. Importantly, NQO1 has been shown to stabilize many proteins, including p53 and p33ING1b, by inhibiting their proteasomal degradation. This review will summarize the biological roles of NQO1 in cancer, with emphasis on recent findings and the potential of NQO1 as a therapeutic target for the cancer therapy.
Keywords
NQO1; Cancer prevention; Cancer therapy;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Siegel D and Ross D (2000) Immunodetection of NAD(P)H: quinone oxidoreductase 1 (NQO1) in human tissues. Free Radical Bio Med 29, 246-253   DOI
2 Asher G, Bercovich Z, Tsvetkov P et al (2005) 20S proteasomal degradation of ornithine decarboxylase is regulated by NQO1. Mol Cell 17, 645-655   DOI
3 Itoh K, Chiba T, Takahashi S et al (1997) An Nrf2:small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236, 313-322   DOI
4 Li Y and Jaiswal AK (1994) Human antioxidant response element mediated regulation of type 1 NAD(P)H: quinone oxidoreductase gene expression. Eur J Biochem 226, 31-39   DOI
5 Vasiliou V, Theurer MJ, Puga A et al (1994) Mouse dioxin-inducible NAD(P)H: menadione oxidoreductase: NMO1 cDNA sequence and genetic differences in mRNA levels. Pharmacogenetics 4, 341-348   DOI
6 Robertson JA, Chen H and Nebert DW (1986) NAD(P)H: menadione oxidoreductase. Novel purification of enzyme, cDNA and complete amino acid sequence and gene regulation. J Biol Chem 261, 15794-15799
7 Wasserman WW and Fahl WE (1997) Functional antioxidant responsive elements. Proc Natl Acad Sci U S A 94, 5361-5366   DOI
8 Li Y, Paonessa JD and Zhang Y (2012) Mechanism of chemical activation of Nrf2. PLoS One 7, e35122   DOI
9 Landers JP and Bunce NJ (1991) The Ah receptor and the mechanism of dioxin toxicity. Biochem J 276, 273-287   DOI
10 Kumaki K, Jensen NM, Shire JGM et al (1977) Genetic differences in induction of cytosol reduced-NAD(P): menadione oxidoreductase and microsomal aryl hydrocarbon hydroxylase in the mouse. J Biol Chem 252, 157-165
11 Radjendirane V and Jaiswal (1999) Antioxidant response element-mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induction of human NAD(P)H:quinone oxidoreductase 1 gene expression. Biochem Pharmacol 58, 1649-1655   DOI
12 Sporn MB (1996) The war on cancer. Lancet 347, 1377-1381   DOI
13 Rothman N, Smith MT, Hayes RB et al (1997) Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C → T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res 57, 2839-2842
14 Kensler TW (1997) Chemoprevention by inducers of carcinogen detoxication enzymes. Environ. Health Perspect 105, 965-970   DOI
15 Fahey JW, Talalay P (1999) Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. Food Chem Toxicol 37, 973-979   DOI
16 Siegel D, Anwar A, Winski SL et al (2001) Rapid polyubiquitination and proteasomal degradation of a mutant from of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol 59, 263-268   DOI
17 Malkinson AM, Siegel D, Forrest DL et al (1992) Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cl. Cancer Res 52, 4752-4757
18 Siegel D and Ross D (2000) Immunodetection ofNAD(P): quinone oxidoreductase 1 (NQO1) in human tissues. Free Rad Biol Med 29, 246-253   DOI
19 Cancer Genome Atlas Research Network (TCGA) (2012) Comprehensive genomic characterization define human colon and rectal cancer. Nature 487, 330-337   DOI
20 Siegel D, Yan C and Ross D (2012) NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83, 1033-1040   DOI
21 Begleiter A, Robotham E and Leith MK (1992) Role of NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase) in activation of mitomycin C under hypoxia. Mol Pharmacol 41, 677-682
22 Li LH, Clark TD, Cowie CH et al (1977) Effects of geldanamycin and its derivatives on RNA-directed DNA polymerase and infectivity of Rauscher leukemia virus. Cancer Treat Rep 61, 815-824
23 Dong GZ, Youn H, Park MT et al (2009) Heat shock increases expression of NAD(P)H:quinone oxidoreductase (NQO1), mediator of beta-lapachone cytotoxicity, by increasing NQO1 gene activity and via Hsp70-mediated stabilization of NQO1 protein. Int J Hypethermia 25, 477-487   DOI
24 Park MT, Song MJ, Lee H et al (2011) β-lapachone significantly increases the effect of ionizing radiation to cause mitochondrial apoptosis activation in cancer cells. PLoS One 6, e25976   DOI
25 Boveris A, Docampo R, Turrens JF et al (1978) Effect of beta-lapachone on superoxide anion and hydrogen peroxide production in Trypanosoma cruzi. Biochem J 175, 431-439   DOI
26 Guo W, Reigan P, Siegel D et al (2005) Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:-quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res 65, 10006-10015   DOI
27 Khong HT, Dreisbach L, Kindler HL et al (2007) A phase 2 study of ARQ 501 in combination with gemcitabine in adult patients with treatment naïve, unresectable pancre atic adenocarcinoma. ASCO Annual Meeting Proceedings Part I. J Clin Oncol 25, 15017
28 Blanco E, Bey EA, Dong Y et al (2007) Beta-lapachonecontaining PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. J Control Release 122, 365-374   DOI
29 Dong Y, Chin SF, Blanco E et al (2009) Intratumoral delivery of beta-lapachone via polymer implants for prostate cancer therapy. Clin Cancer Res 15, 131-139   DOI
30 Park C, Youn H, Kim H et al (2009) Cyclodextrin-covered gold nanoparticles for targeted delivery of an anti-cancer drug. J Mater Chem 19, 2310-2315   DOI
31 Schlager JJ and Powis G (1990) Cytosilic NAD(P)H: (quinone-acceptor)oxidoreductase in human normal and tumor tissue: effects of cigarette smoking and alchol. Int J Cancer 45, 403-409   DOI
32 Terai K, Dong GZ, Oh ET et al (2009) Cisplatin enhances the anticancer effect of beta-lapachone by upregulating NQO1. Anticancer Drugs 20, 901-909   DOI
33 Nioi P and Hayes JD (2004) Contribution of NAD(P)H: quinoneoxidoreductase 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 555, 149-171   DOI
34 Kaspar JW and Jaiswal AK (2010) Antioxidant-induced phosphorylation of tyrosine 486 leads to rapid nuclear export of Bach 1 that allows Nrf2 to bind to the antitoxidant response element and activated defensive gene expression. J Biol Chem 285, 153-162   DOI
35 Venugopal R and Jaiswal AK (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17, 3145-3156   DOI
36 Ernster L and Navazio F (1958) Soluble diaphorase in animal tissues. Acta Chem Scand 12, 595-602   DOI
37 Surh YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3, 768-780   DOI
38 Chen H, Lum A, Seifried A et al (1999) Association of the NAD(P)H:quinone oxidoreducatase 609C→T polymorphism with a decreased lung cancer risk. Cancer Res 59, 3045-3048
39 Peng Q, Lu Y, Lao X et al (2014) The NQO1 Pro187Ser polymorphism and breast cancer susceptibility: evidence from an updated meta-analysis. Diagn Pathol doi:10.1186/1746-1596-9-100   DOI
40 Cornblatt BS, Ye L, Dinkova-Kostova AT et al (2007) Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis 28, 1485-1490   DOI
41 Lin P, Wang HJ, Lee H et al (1999) NAD(P)H:quinone oxidoreductase polymorphism and lung cancer in Taiwna. J Toxicol Environ Health A 58, 187-197   DOI
42 Lewis SJ, Cherry NM, Niven RM et al (2001) Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population. Lung Cancer 34, 177-183   DOI
43 Song SY, Jeong SY, Park HJ et al (2010) Clinical significance of NQO1 C609T polymorphisms after postoperative radiation therapy in completely resected nonsmall cell lung cancer. Lung Cancer 68, 278-282   DOI
44 Hamajima N, Matsuo K, Iwata H et al (2002) NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese. Int J Clin Oncol 7, 103-108
45 Menzel HJ, Sarmanova J, Soucek P et al (2004) Association of NQO1 polymorphsim with spontaneous breast cancer in two independent populations. Br J Cancer 90, 1989-1994   DOI
46 Lajin B and Alachkar A (2013) The NQO1 polymorphsim C609T (Pro187Ser) and cancer susceptibility: a comprehensive meta-analysis. Br J Cancer 109, 1325-1337   DOI
47 Zheng B, Wang Z and Chai R (2014) NQO1 C609T polymorphism and colorectal cancer susceptibility: a metaanalysis. Arch Med Sci 10, 651-660   DOI
48 Anwar A, Siegel D, Kepa JK et al (2002) Interaction of the molecular chaperone Hsp70 with human NAD(P)H: quinone oxidoreductase 1. J Biol Chem 277, 14060-14067   DOI
49 Fan Y, Hu D, Feng B and Wang W (2014) The NQO1 C609T polymorphism and hepatocellular carcinoma risk. Tumour Biol 35, 7343-7350   DOI
50 Cho CG, Lee SK, Nam SY et al (2006) Association of the GSTP1 and NQO1 polymorphsms and head and neck squamous cell carcinoma risk. J Korean Med Sci 21, 1075-1079   DOI
51 Traver RD, Horikoshi T, Danenberg KD et al (1992) NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res 52, 797-802
52 Ma Y, Kong J, Yan G et al (2014) NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 14, 414. doi:10.1186/1471-2407-14-414   DOI
53 Yang Y, Zhang Y, Wu Q et al (2014) Clinical implications of high NQO1 expression in breast cancers. J Exp Clin Cancer Res 33,14. doi: 10.1186/1756-9966-33-14   DOI
54 Cresteil T and Jaiswal AK (1991) High levels of expression of the NAD(P)H: quinone oxidoreductase (NQO1) gene in tumor cells compared to normal cells of the same origin. Biochem Pharmacol 42, 1021-1027   DOI
55 Siegel D, Franklin WA and Ross D (1998) Immunohistochemical detection of NAD(P)H: quinone oxidoreductase in human lung and lung tumors. Clin Cancer Res 4, 2065-2070
56 Winski SL, Koutalos Y, Bentley DL et al (2002) Subcellular localization of NAD(P)H:quinone oxidoreducatase 1 in human cancer cells. Cancer Res 62, 1420-1424
57 Ross D, Kepa JK, Winski SL et al (2000) NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129, 77-97   DOI
58 Beall HD, Murphy AM, Siegel D et al (1995) Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines. Mol Pharmacol 48, 499-504
59 Siegel D, Gustafson DL, Dehn DL et al (2004) NAD(P)H: quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 65, 1238-1247   DOI
60 Gibson NW, Hartley JA, Butler J et al (1992) Relationship between DT-diaphorase mediated metabolism of a series of aziridinyl benzoquinones and DNA damage and cytotoxicity. Mol Pharmacol 42, 531-536
61 Gustafson DL, Beall HD, Bolton EM et al (1996) Expression of human NQO1 (DT-diaphorase) in Chinese hamster ovary cells: effect on the toxicity of antitumor quinones. Mol Pharmacol 50, 728-735
62 Mikami K, Naito M, Tomida A et al (1996) DT-diaphorase as a critical determinant of sensitivity to mitomycin C in human colon and gastric carcinoma cell lines. Cancer Res 56, 2823-2826
63 Ross D, Beall HD, Siegel D et al (1996) Enzymology of bioreductive drug activation. Br J Cancer 74 (suppl. XXVII), S1-S8   DOI
64 Kelland LR, Sharp SY, Rogers PM et al (1999) DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst 91, 1940-1949   DOI
65 Goetz MP, Toft D, Reid J et al (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23, 1078-1087   DOI
66 Choi EK, Terai K, Ji IM et al (2007) Upregulation of NAD(P)H:Quinone Oxidoreductase by radiation potentiates the effect of bioreductive β -lapachone on cancer cells. Neoplasia 9, 634-642   DOI
67 Winski SL, Swann E, Hargreaves RH et al (2001) Relationship between NAD(P)H:quinone oxidoreductase 1 (NQO1) levels in a series of stably transfected cell lines and susceptibility to antitumor quinones. Biochem Pharmacol 61, 1509-1516   DOI
68 Loadman PM, Bibby MC, and Phillips RM (2002) Pharmacological approach towards the development of indole quinone bioreductive drugs used on the clinically inactive agent EO9. Br J Pharmacol 137, 701-709   DOI
69 Park HJ, Ahn KJ, Ahn SD et al (2005) Susceptibility of cancer cells to beta-lapachone is enhanced by ionizing radiation. Int J Radiat Oncol Biol Phys 61, 212-219   DOI
70 Suzuki M, Amano M, Choi J et al (2006) Synergistic effects of radiation and beta-lapachone in DU-145 human prostate cancer cells in vitro. Radiat Res 165, 525-531   DOI
71 Park HJ, Choi EK, Choi J et al (2005) Heat-induced up-regulation of NAD(P)H: quinone oxidoreductase potentiates anticancer effects of beta-lapachone. Clin Cancer Res 11, 8866-8871   DOI
72 Song CW, Chae JJ, Choi EK et al (2008) Anti-cancer effect of bio-reductive drug beta-lapachon is enhanced by activating NQO1 with heat shock. Int J Hyperthermia 24, 161-169   DOI
73 Dinkova-Kostova A and Talalay P (2010) NAD(P)H:quinone acceptor oxidoreducatase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 501, 116-123   DOI
74 Anwar A, Dehn D, Siegel D et al (2003) Interaction of human NAD(P)H:Quinone Oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. J Biol Chem 278, 10368-10373   DOI
75 Garate M, Wong RPC, Campos EI et al (2008) NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of the tumour suppressor p33ING1b. EMBO Rep 9, 576-581   DOI
76 Asher G, Tsvetkov P, Kahana C et al (2005) A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes Dev 19, 316- 321   DOI
77 Asher G, Lotem J, Kama R et al (2001) NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci U S A 99, 3099-3104   DOI
78 Patrick BA and Jaiswal AK (2012) Stress-induced NQO1 controls stability of C/EBP against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer. Oncogene 31, 4362-4371   DOI
79 Cuendet M, Oteham CP, Moon RC et al (2006) Quinone reductase induction as a biomarker for cancer chemoprevention. J Nat Prod 69, 460-463   DOI
80 Zhu H and Li Y (2012) NAD(P)H:quinone oxidoreductase 1 and its potential protective role in cardiovascular diseases and related conditions. Cardiovasc Toxicol 12, 39-45   DOI
81 Williams JB, Lu AYH, Cameron RG et al (1986) Rat liver NAD(P)H:quinone reductase. J Biol Chem 261, 5524-5528
82 Jaiswal AK, McBride OW, Adensik M et al (1988) Human dioxin-inducible cytosolic NAD(P)H:quinone oxidoreductase. J Biol Chem 263, 13572-13578
83 Nebert DW, Roe AL, Vandale SE et al (2002) NAD(P)H: quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. Genet Med 4, 62-70   DOI
84 Ross D, Kepa JK, Winski SL et al (2000) NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129, 77-97   DOI
85 Wefers H and Sies H (1983) Hepatic low-level chemiluminescence during redox cycling of menadione and the menadione-glutathion conjugate: relation to glutathione and NAD(P)H:quinone reductase (DT-diaphorase) activity. Arch Biochem Biophys 224, 568-578   DOI
86 Atia A, Alrawaiq N and Abdullah A (2014) A review of NAD(P)H:quinone oxidoreductase 1 (NQO1); A multifunctional antioxidant enzyme. J Appl Pharm Sci 4, 118-122
87 Lind C, Cadenas E, Hochstein P et al (1990) DT-diaphorase: purification properties and function. Methods Enzymol 186, 287-301   DOI
88 Li R, Bianchet MA, Talalay P and 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 U S A 92, 8846-8850   DOI
89 Talalay P, and Dinkova-Kostova AT (2004) Role of nicotinamide quinone oxidoreductase 1 (NQO1) in protection against toxicity of electrophiles and reactive oxygen intermediates. Meth Enzymol 382, 355-364   DOI
90 Cenas N, Anusevicius Z, Nivinskas H et al (2004) Structure-activity relationships in two-electron reduction of quinones. Meth Enzymol 382, 258-277   DOI
91 Ross D (2004) Quinone reductases multitasking in the metabolic world. Drug Metabol Rev 36, 639-654   DOI