Browse > Article
http://dx.doi.org/10.5352/JLS.2014.24.1.98

NAD(P)H Quinone Oxidoreductase 1 (NQO1) as a Cancer Therapeutic Target  

Park, Eun Jung (Department of Immunology, School of Medicine, Keimyung University)
Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University)
Publication Information
Journal of Life Science / v.24, no.1, 2014 , pp. 98-103 More about this Journal
Abstract
NAD(P)H quinone oxidoreductase 1 (NQO1) is a flavoprotein that catalyzes the two electron reduction of diverse substrates, including quinones. It uses NADH or NADPH as a cofactor for enzymatic machinery. In the metabolism of quinones, NQO1 has two conflicting functions because of the different stability of converted hydroquinones. The stable form of hydroquinone is excreted from cells by conjugation with glutathione or glucuronic acid. The unstable form of hydroquinone induces cell death by induction of oxidative stress and DNA damage. Certain quinones known as bio-reductive agents have a cytotoxic function following reduction by NQO1. Bio-reductive agents, such as ${\beta}$-lapachone or mitomycin C, induce the depletion of NAD(P)H and the generation of oxidative stress in an NQO1-dependent manner. NQO1 is highly expressed in several cancer tissues. Therefore, NQO1 is a good therapeutic target for cancer treatment with bio-reductive agents.
Keywords
Cancer; cell death; NAD(P)H Quinone Oxidoreductase 1 (NQO1); oxidative stress; ${\beta}$-lapachone;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Seow, H. A., Penketh, P. G., Belcourt, M. F., Tomasz, M., Rockwell, S. and Sartorelli, A. C. 2004. Nuclear overexpression of NAD(P)H: quinone oxidoreductase 1 in Chinese hamster ovary cells increases the cytotoxicity of mitomycin C under aerobic and hypoxic conditions. J Biol Chem 279, 31606-31612.   DOI
2 Siegel, D. and Ross, D. 2000. Immunodetection of NAD(P) H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med 29, 246-253.   DOI   ScienceOn
3 Smith, D., Martin, L. and Wallin, R. 1988. Human DT-diaphorase, a potential cancer protecting enzyme. Its purification from abdominal adipose tissue. Cancer Lett 42, 103-112.   DOI
4 Song, C. W., Chae, J. J., Choi, E. K., Hwang, T. S., Kim, C., Lim, B. U. and Park, H. J. 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
5 Weller, M., Winter, S., Schmidt, C., Esser, P., Fontana, A., Dichgans, J. and Groscurth, P. 1997. Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95- mediated apoptosis by camptothecin and beta-lapachone. Int J Cancer 73, 707-714.   DOI   ScienceOn
6 Thor, H., Smith, M. T., Hartzell, P., Bellomo, G., Jewell, S. A. and 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, 12419-12425.
7 Tzeng, H. P., Ho, F. M., Chao, K. F., Kuo, M. L., Lin-Shiau, S. Y. and Liu, S. H. 2003. beta-Lapachone reduces endotoxin- induced macrophage activation and lung edema and mortality. Am J Respir Crit Care Med 168, 85-91.   DOI
8 Vasiliou, V., Ross, D. and Nebert, D. W. 2006. Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. Hum Genomics 2, 329-335.   DOI
9 Williams, J. B., Lu, A. Y., Cameron, R. G. and Pickett, C. B. 1986. Rat liver NAD(P)H: quinone reductase. Construction of a quinone reductase cDNA clone and regulation of quinone reductase mRNA by 3-methylcholanthrene and in persistent hepatocyte nodules induced by chemical carcinogens. J Biol Chem 261, 5524-5528.
10 Winski, S. L., Koutalos, Y., Bentley, D. L. and Ross, D. 2002. Subcellular localization of NAD(P)H: quinone oxidoreductase 1 in human cancer cells. Cancer Res 62, 1420-1424.
11 Woo, H. J. and Choi, Y. H. 2005. Growth inhibition of A549 human lung carcinoma cells by beta-lapachone through induction of apoptosis and inhibition of telomerase activity. Int J Oncol 26, 1017-1023.
12 Woo, H. J., Park, K. Y., Rhu, C. H., Lee, W. H., Choi, B. T., Kim, G. Y., Park, Y. M. and Choi, Y. H. 2006. Beta-lapachone, a quinone isolated from Tabebuia avellanedae, induces apoptosis in HepG2 hepatoma cell line through induction of Bax and activation of caspase. J Med Food 9, 161-168.   DOI
13 Choudry, G. A., Stewart, P. A., Double, J. A., Krul, M. R., Naylor, B., Flannigan, G. M., Shah, T. K., Brown, J. E. and Phillips, R. M. 2001. A novel strategy for NQO1 (NAD (P)H: quinone oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of EO9. Br J Cancer 85, 1137-1146.   DOI
14 Amzel, L. M., Bryant, S. H., Prochaska, H. J. and Talalay, P. 1986. Preliminary crystallographic X-ray data for an NAD(P)H:quinone reductase from mouse liver. J Biol Chem 261, 1379.
15 Begleiter, A., El-Gabalawy, N., Lange, L., Leith, M. K., Guziec, L. J. and Guziec, F. S., Jr. 2009. A model for NAD (P)H: quinoneoxidoreductase 1 (NQO1) targeted individualized cancer chemotherapy. Drug Target Insights 4, 1-8.
16 Belinsky, M. and Jaiswal, A. K. 1993. NAD(P)H: quinone oxidoreductase1 (DT-diaphorase) expression in normal and tumor tissues. Cancer Metastasis Rev 12, 103-117.   DOI   ScienceOn
17 D'Anneo, A., Augello, G., Santulli, A., Giuliano, M., di Fiore, R., Messina, C., Tesoriere, G. and Vento, R. 2010. Paclitaxel and beta-lapachone synergistically induce apoptosis in human retinoblastoma Y79 cells by downregulating the levels of phospho-Akt. J Cell Physiol 222, 433-443.   DOI
18 Boveris, A., Docampo, R., Turrens, J. F. and Stoppani, A. O. 1978. Effect of beta-lapachone on superoxide anion and hydrogen peroxide production in Trypanosoma cruzi. Biochem J 175, 431-439.
19 Choi, B. T., Cheong, J. and Choi, Y. H. 2003. beta- Lapachone-induced apoptosis is associated with activation of caspase-3 and inactivation of NF-kappaB in human colon cancer HCT-116 cells. Anticancer Drugs 14, 845-850.
20 Cresteil, T. and Jaiswal, A. K. 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   ScienceOn
21 Danson, S., Ward, T. H., Butler, J. and Ranson, M. 2004. DT-diaphorase: a target for new anticancer drugs. Cancer Treat Rev 30, 437-449.   DOI   ScienceOn
22 Ernster, L., Danielson, L. and Ljunggren, M. 1962. DT diaphorase. I. Purification from the soluble fraction of rat-liver cytoplasm, and properties. Biochim Biophys Acta 58, 171-188.   DOI
23 De Haan, L. H., Boerboom, A. M., Rietjens, I. M., van Capelle, D., De Ruijter, A. J., Jaiswal, A. K. and Aarts, J. M. 2002. A physiological threshold for protection against menadione toxicity by human NAD(P)H:quinone oxidoreductase (NQO1) in Chinese hamster ovary (CHO) cells. Biochem Pharmacol 64, 1597-1603.   DOI
24 Gonzalez, F. J. 1988. The molecular biology of cytochrome P450s. Pharmacol Rev 40, 243-288.
25 Don, M. J., Chang, Y. H., Chen, K. K., Ho, L. K. and Chau, Y. P. 2001. Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells. Mol Pharmacol 59, 784-794.
26 Dubin, M., Fernandez Villamil, S. H. and Stoppani, A. O. 2001. Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use. Medicina (B Aires) 61, 343-350.
27 Ernster, L. and Navazio, F. 1958. Soluble diaphorase in animal tissue. Acta Chem Scand 12, 595-602.   DOI
28 Höjeberg, B., Blomberg, K., Stenberg, S. and Lind, C. 1981. Biospecific adsorption of hepatic DT-diaphorase on immobilized dicoumarol: I. Purification of cytosolic DT-diaphorase from control and 3-methylcholanthrene-treated rats. Archives of biochemistry and biophysics 207, 205-216.   DOI   ScienceOn
29 Jackson, J., Higo, T., Hunter, W. and Burt, H. 2008. Topoisomerase inhibitors as anti-arthritic agents. Inflammation Res 57, 126-134.   DOI
30 Hartner, L., Rosen, L., Hensley, M., Mendelson, D., Staddon, A., Chow, W., Kovalyov, O., Ruka, W., Skladowski, K. and Jagiello-Gruszfeld, A. 2007. Phase 2 dose multi-center, open-label study of ARQ 501, a checkpoint activator, in adult patients with persistent, recurrent or metastatic leiomyosarcoma (LMS). J Clin Oncol 25, 20521.
31 Hodnick, W. F., Kalyanaraman, B., Pritsos, C. A. and Pardini, R. S. 1988. The production of hydroxyl and semiquinone free radicals during the autoxidation of redox active flavonoids. Basic Life Sci 49, 149-152.
32 Huang, L. and Pardee, A. B. 1999. beta-lapachone induces cell cycle arrest and apoptosis in human colon cancer cells. Mol Med 5, 711-720.
33 Kawecki, A., Adkins, D., Cunningham, C., Vokes, E., Yagovane, D., Dombal, G., Koralewski, P., Hotko, Y. and Vladimirov, V. 2007. A phase II study of ARQ 501 in patients with advanced squamous cell carcinoma of the head and neck. J Clin Oncol 25, 16509.
34 Jaiswal, A. K., Burnett, P., Adesnik, M. and McBride, O. W. 1990. Nucleotide and deduced amino acid sequence of a human cDNA (NQO2) corresponding to a second member of the NAD(P)H: quinone oxidoreductase gene family. Extensive polymorphism at the NQO2 gene locus on chromosome 6. Biochemistry 29, 1899-1906.   DOI   ScienceOn
35 Jaiswal, A. K., McBride, O. W., Adesnik, M. and Nebert, D. W. 1988. Human dioxin-inducible cytosolic NAD(P) H: menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16. J Biol Chem 263, 13572-13578.
36 Joseph, P. and Jaiswal, A. K. 1994. NAD(P)H: quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo[a]pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proc Natl Acad Sci USA 91, 8413-8417.   DOI
37 Lai, C. C., Liu, T. J., Ho, L. K., Don, M. J. and Chau, Y. P. 1998. beta-Lapachone induced cell death in human hepatoma (HepA2) cells. Histol Histopathol 13, 89-97.
38 Keyes, S. R., Fracasso, P. M., Heimbrook, D. C., Rockwell, S., Sligar, S. G. and Sartorelli, A. C. 1984. Role of NADPH: cytochrome c reductase and DT-diaphorase in the biotransformation of mitomycin C1. Cancer Res 44, 5638-5643.
39 Kumi-Diaka, J. 2002. Chemosensitivity of human prostate cancer cells PC3 and LNCaP to genistein isoflavone and beta- lapachone. Biol Cell 94, 37-44.   DOI   ScienceOn
40 Lewis, A. M., Ough, M., Hinkhouse, M. M., Tsao, M. S., Oberley, L. W. and Cullen, J. J. 2005. Targeting NAD(P)H: quinone oxidoreductase (NQO1) in pancreatic cancer. Mol Carcinog 43, 215-224.   DOI
41 Li, C. J., Li, Y. Z., Pinto, A. V. and Pardee, A. B. 1999. Potent inhibition of tumor survival in vivo by beta-lapachone plus taxol: combining drugs imposes different artificial checkpoints. Proc Natl Acad Sci USA 96, 13369-13374.   DOI   ScienceOn
42 Li, C. J., Wang, C. and Pardee, A. B. 1995. Induction of apoptosis by beta-lapachone in human prostate cancer cells. Cancer Res 55, 3712-3715.
43 Li, Y., Li, C. J., Yu, D. and Pardee, A. B. 2000. Potent induction of apoptosis by beta-lapachone in human multiple myeloma cell lines and patient cells. Mol Med 6, 1008-1015.
44 Lind, C., Cadenas, E., Hochstein, P. and Ernster, L. 1990. DT-diaphorase: purification, properties, and function. Methods Enzymol 186, 287-301.   DOI
45 Long, D. J., 2nd, Waikel, R. L., Wang, X. J., Roop, D. R. and Jaiswal, A. K. 2001. NAD(P)H: quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[ a]-anthracene-induced carcinogenesis in mouse skin. J Natl Cancer Inst 93, 1166-1170.   DOI
46 Lind, C., Hochstein, P. and Ernster, L. 1982. DT-diaphorase as a quinone reductase: a cellular control device against semiquinone and superoxide radical formation. Arch Biochem Biophys 216, 178-185.   DOI   ScienceOn
47 Liu, T. J., Lin, S. Y. and Chau, Y. P. 2002. Inhibition of poly(ADP-ribose) polymerase activation attenuates beta-lapachone-induced necrotic cell death in human osteosarcoma cells. Toxicol Appl Pharmacol 182, 116-125.   DOI
48 Menacho-Marquez, M. and Murguia, J. R. 2006. Beta-lapachone activates a Mre11p-Tel1p G1/S checkpoint in budding yeast. Cell Cycle 5, 2509-2516.   DOI
49 Long, D. J., 2nd, Waikel, R. L., Wang, X. J., Perlaky, L., Roop, D. R. and Jaiswal, A. K. 2000. NAD(P)H: quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a) pyrene-induced mouse skin carcinogenesis. Cancer Res 60, 5913-5915.
50 Martin, L. F., Patrick, S. D. and Wallin, R. 1987. DT-diaphorase in morbidly obese patients. Cancer Lett 36, 341-347.   DOI
51 Mikami, K., Naito, M., Tomida, A., Yamada, M., Sirakusa, T. and Tsuruo, T. 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.
52 Nishiyama, T., Izawa, T., Usami, M., Ohnuma, T., Ogura, K. and Hiratsuka, A. 2010. Cooperation of NAD(P)H: quinone oxidoreductase 1 and UDP-glucuronosyltransferases reduces menadione cytotoxicity in HEK293 cells. Biochem Biophys Res Commun 394, 459-463.   DOI
53 Park, H. J., Choi, E. K., Choi, J., Ahn, K. J., Kim, E. J., Ji, I. M., Kook, Y. H., Ahn, S. D., Williams, B., Griffin, R., Boothman, D. A., Lee, C. K. and Song, C. W. 2005. Heat-induced up-regulation of NAD(P)H: quinone oxidoreductase potentiates anticancer effects of beta-lapachone. Clin Cancer Res 11, 8866-8871.   DOI   ScienceOn
54 Pardee, A. B., Li, Y. Z. and Li, C. J. 2002. Cancer therapy with beta-lapachone. Curr Cancer Drug Targets 2, 227-242.   DOI   ScienceOn
55 Park, E. J., Choi, K. S. and Kwon, T. K. 2011. beta- Lapachone-induced reactive oxygen species (ROS) generation mediates autophagic cell death in glioma U87 MG cells. Chem Biol Interact 189, 37-44.   DOI
56 Schaffner-Sabba, K., Schmidt-Ruppin, K. H., Wehrli, W., Schuerch, A. R. and Wasley, J. W. 1984. beta-Lapachone: synthesis of derivatives and activities in tumor models. J Med Chem 27, 990-994.   DOI
57 Pink, J. J., Planchon, S. M., Tagliarino, C., Varnes, M. E., Siegel, D. and Boothman, D. A. 2000. NAD(P)H: quinone oxidoreductase activity is the principal determinant of beta- lapachone cytotoxicity. J Biol Chem 275, 5416-5424.   DOI   ScienceOn
58 Prochaska, H. J. and Talalay, P. 1986. Purification and characterization of two isofunctional forms of NAD(P)H: quinone reductase from mouse liver. J Biol Chem 261, 1372-1378.
59 Radjendirane, V., Joseph, P., Lee, Y. H., Kimura, S., Klein-Szanto, A. J., Gonzalez, F. J. and Jaiswal, A. K. 1998. Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J Biol Chem 273, 7382-7389.   DOI   ScienceOn
60 Raftell, M. and Blomberg, K. 1980. Immunochemical studies on two DT diaphorase active antigens isolated from rat liver cytosol by affinity chromatography. Arch Biochem Biophys 199, 165-171.   DOI
61 Ross, D., Kepa, J. K., Winski, S. L., Beall, H. D., Anwar, A. and Siegel, D. 2000. NAD(P)H: quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129, 77-97.   DOI
62 Ross, D. and Siegel, D. 2004. NAD(P)H: quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics. Methods Enzymol 382, 115-144.   DOI
63 Segura-Aguilar, J., Kaiser, R. and Lind, C. 1992. Separation and characterization of isoforms of DT-diaphorase from rat liver cytosol. Biochim Biophys Acta 1120, 33-42.   DOI
64 Ough, M., Lewis, A., Bey, E. A., Gao, J., Ritchie, J. M., Bornmann, W., Boothman, D. A., Oberley, L. W. and Cullen, J. J. 2005. Efficacy of beta-lapachone in pancreatic cancer treatment: exploiting the novel, therapeutic target NQO1. Cancer Biol Ther 4, 95-102.   DOI
65 Bey, E. A., Reinicke, K. E., Srougi, M. C., Varnes, M., Anderson, V. E., Pink, J. J., Li, L. S., Patel, M., Cao, L., Moore, Z., Rommel, A., Boatman, M., Lewis, C., Euhus, D. M., Bornmann, W. G., Buchsbaum, D. J., Spitz, D. R., Gao, J. and Boothman, D. A. 2013. Catalase abrogates beta-lapachone- induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers. Mol Cancer Ther 12, 2110-2120.   DOI
66 Bey, E. A., Bentle, M. S., Reinicke, K. E., Dong, Y., Yang, C. R., Girard, L., Minna, J. D., Bornmann, W. G., Gao, J. and Boothman, D. A. 2007. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci USA 104, 11832-11837.   DOI   ScienceOn
67 Gupta, D., Podar, K., Tai, Y. T., Lin, B., Hideshima, T., Akiyama, M., LeBlanc, R., Catley, L., Mitsiades, N., Mitsiades, C., Chauhan, D., Munshi, N. C. and Anderson, K. C. 2002. Beta-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells. Exp Hematol 30, 711-720.   DOI
68 Pink, J. J., Wuerzberger-Davis, S., Tagliarino, C., Planchon, S. M., Yang, X., Froelich, C. J. and Boothman, D. A. 2000. Activation of a cysteine protease in MCF-7 and T47D breast cancer cells during beta-lapachone-mediated apoptosis. Exp Cell Res 255, 144-155.   DOI   ScienceOn
69 Kikuchi, T., Sugiura, Y. and Komiyama, T. 1981. Generation of semiquinone radical from carbazilquinone by NADPHcytochrome P-450 reductase. Biochem Pharmacol 30, 1717-1718.   DOI