Cancer Treatment Reviews
Volume 30, Issue 5 , Pages 437-449 , August 2004

DT-diaphorase: a target for new anticancer drugs

  • S Danson

      Affiliations

    • Paterson Institute for Cancer Research, Manchester, UK
    • Department of Medical Oncology, Manchester, UK
    • Corresponding Author InformationCorresponding author. Present address: Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. Fax: +44-161-446-3299
    • ,
  • T.H Ward

      Affiliations

    • Paterson Institute for Cancer Research, Manchester, UK
    • ,
  • J Butler

      Affiliations

    • Salford University, Manchester, UK
    • ,
  • M Ranson

      Affiliations

    • Paterson Institute for Cancer Research, Manchester, UK
    • Department of Medical Oncology, Manchester, UK

References 

  1. Ernster L, Navazio F. Soluble diaphorase in animal tissues. Acta Chemica Scandanavia. 1958;12:595–602
  2. Gutierrez PL. The role of NAD(P)H oxidoreductase (DT-diaphorase) in the bioactivation of quinone-containing antitumour agents: a review. Free Rad. Biol. Med. 2000;29:263–275
  3. Ross D, Kepa J, Winski S, Beall HD, Anwar A, Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, gene regulation and genetic polymorphisms. Chem-Biol. Int. 2000;129:77–97
  4. Rauth AM, Goldberg Z, Misra V. DT-diaphorase: possible roles in cancer chemotherapy and carcinogenesis. Oncol. Res. 1997;9:339–349
  5. Ross D, Beall H, Traver R, Siegel D, Phillips RM, Gibson NW. Bioactivation of quinones by DT-diaphorase, molecular, biochemical and chemical studies. Oncol. Res. 1994;6:493–500
  6. Ross D, Siegel D, Beall H, Prakash AS, Mulcahy RT, Gibson NW. DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C. Cancer Metastasis Rev. 1993;12:83–101
  7. Riley RJ, Workman P. DT-diaphorase and cancer chemotherapy. Biochem. Pharmacol. 1992;43:1657–1669
  8. Eliasson M, Bostrom M, Depierre JW. Levels and subcellular distributions of detoxifying enzymes in the ovarian corpus luteum of the pregnant and non-pregnant pig. Biochem. Pharmacol. 1999;58:1287–1292
  9. Danielson L, Ernster L, Ljunggren M. Selective extraction of DT-diaphorase from mitochondria and microsomes. Acta Chem. Scand. 1960;14:1837–1838
  10. Conover TE, Ernster L. DT-diaphorase IV. Coupling of extramitochondrial reduced pyridine nucleotide oxidation to mitochondrial respiratory chain. Biochem. Biophys. Acta. 1968;67:268–280
  11. Edlund C, Elhrmammer A, Dallner G. Distribution of newly synthesised DT-diaphorase in rat liver. Biosci. Rep. 1982;2:861–865
  12. Winski SL, Koutalos Y, Bentley DL, Ross D. Subcellular localisation of NAD(P)H:quinone oxidoreductase 1 in human cancer cells. Cancer Res. 2002;62:1420–1424
  13. Siegel D, Gibson NW, Preusch PC, Ross D. Metabolism of NAD(P)H: (quinone acceptor) oxidoreductase (DT-diaphorase): role in diaziquone-induced DNA damage and cytotoxicity in human colon carcinoma cells. Cancer Res. 1990;50:7293–7300
  14. Beyer RE, Segura-Aguilar J, Di Bernardo S, et al.  The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. PNAS. 1996;93:2528–2532
  15. Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D. The reduction of alpha-tocopherolquinone by human NAD(P)H:quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant. Mol. Pharmacol. 1997;52:300–305
  16. Jaiswal AK. Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free Rad. Biol. Med. 2000;29:254–262
  17. Benson AN, Hunckler MJ, Talalay P. Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. PNAS. 1980;77:5216–5220
  18. Schlager JJ, Powis G. Cytosolic NAD(P)H:(quinone-acceptor) oxidoreductase in human and normal tissue: effects of cigarette smoking and alcohol. Int. J. Cancer. 1990;45:403–409
  19. Chen S, Knox R, Wu K, Deng PSK, Zhou D. Molecular basis of the catalytic differences among DT-diaphorase of human, rat, and mouse. J. Biol. Chem. 1997;272:1437–1439
  20. Edwards YH, Potter J, Hopkinson DA. Human FAD-dependent NAD(P)H diaphorase. Biochem. J. 1980;187:429–436
  21. Jaiswal AK, McBride OW, Adesnik M, Nebert DW. Human dioxin-inducible cytosolic NAD(P)H:menadione oxidoreductase cDNA sequence and localization of gene to chromosome 16. J. Biol. Chem. 1988;263:13572–13578
  22. Jaiswal AK. Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin. Biochemistry. 1991;30:10647–10653
  23. Joseph P, Xie T, Xu Y, Jaiswal AK. NAD(P)H:quinone oxidoreductase 1 (DT-diaphorase): expression, regulation and role in cancer. Oncol. Res. 1994;6:525–532
  24. Yao K, O'Dwyer PJ. Involvement of NF-κB in the induction of NAD(P)H:quinone oxidoreductase (DT-diaphorase) by hypoxia, oltipraz and mitomycin C. Biochem. Pharmacol. 1995;49:275–282
  25. Montano MM, Jaiswal AK, Katzenellenbogen BS. Transcriptional regulation of the human quinone reductase gene by antioestrogen-liganded oestrogen receptor-α and oestrogen receptor-β. Oncogene. 1998;273:25443–25449
  26. Jaiswal AK, Burnett P, Adesnik M, McBride OW. 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. 1990;29:1899–1906
  27. Chen S, Wu K, Knox R. Structure-function studies of DT-diaphorase (NQO1) and NRH:quinone oxidoreductase (NQO2). Free Rad. Biol. Med. 2000;29:276–284
  28. Long DJ, Jaiswal AK. NRH:quinone oxidoreductase 2 (NQO2). Chem. Biol. Int. 2000;129:99–112
  29. Traver RD, Horikoshi T, Danenberg KD, et al.  NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterisation of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res. 1992;52:797–802
  30. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid polyubiquination and proteosomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol. Pharmacol. 2001;59:263–268
  31. Li R, Bianchet MA, Talalay P, Amzel LM. The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. PNAS. 1995;92:8846–8850
  32. Kelsey KT, Ross D, Traver RD, et al.  Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anticancer chemotherapy. Br. J. Cancer. 1997;76:852–854
  33. Misra V, Grondin A, Klamut HJ, Rauth AM. Assessment of the relationship between genotypic status of a DT-diaphorase point mutation and enzymatic activity. Br. J. Cancer. 2000;83:998–1002
  34. Gaedigk A, Tyndale RF, Jurima-Romet M, Sellers EM, Grant DM, Leeder JS. NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations. Pharmacogenetics. 1998;8:305–313
  35. Pan SS, Han Y, Farabaugh P, Xia H. Implication of alternative splicing for expression of a variant NAD(P)H:quinone oxidoreductase-1 with a single nucleotide polymorphism at 465C>T. Pharmacogenetics. 2002;12:479–488
  36. Yoneda Y, Hieda M, Nagoshi E, Miyamoto Y. Nucleocytoplasmic protein transport and recycling of Ran. Cell Struct. Funct. 1999;24:425–433
  37. Anwar A, Siegel D, Kepa JK, Ross D. Interaction of the molecular chaperone HSP70 with human NAD(P)H:quinone oxidoreductase 1. J. Biol. Chem. 2002;277:14060–14067
  38. Qiu X, Schonthal AH, Cadenas E. Anticancer quinones induce pRb-preventable G2/M cell cycle arrest and apoptosis. Free Rad. Biol. Med. 1998;24:848–854
  39. Ngo EO, Nutter LM, Sura T, Gutierrez PL. Induction of p53 by the concerted actions of aziridine and quinone moieties of diaziquone. Chem. Res. Toxixol. 1988;11:360–368
  40. Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilises p53 through a distinct pathway. PNAS. 2002;99:3099–3104
  41. Schor NA, Rice BF, Huseby RA. Dehydrogenation of reduced pyridine nucleotides by leydig cell tumours of the rat testis. Proc. Soc. Exp. Biol. Med. 1976;151:418–421
  42. Schor NA, Morris HP. The activity of DT-diaphorase in experimental hepatomas. Biochem. Biophys. Acta. 1977;2:5–9
  43. Schor NA, Ogawa K, Lee G, Farber E. The use of the DT-diaphorase for the detection of foci of early neoplastic transformation in rat liver. Cancer Lett. 1978;5:167–171
  44. Becker FF, Stout DL. A constitutive deficiency in the monooxygenase system of spontaneous mouse liver tumours. Carcinogenesis. 1984;5:785–788
  45. Berger MS, Talcott RE, Rosenblum ML. Use of quinones in brain tumour therapy: preliminary results of preclinical laboratory investigations. J. Toxicol. Env. Health. 1985;16:713–719
  46. Beyer RE, Segura-Aguilar JE, Ernster L. The anticancer enzyme DT-diaphorase is induced selectively in the liver during ascites hepatoma growth. Anticancer Res. 1988;8:233–238
  47. Schor NA, Cornelisse CJ. Biochemical and quantitative histochemical study of reduced pyridine nucleotide dehydrogenation by human colon carcinomas. Cancer Res. 1983;43:4850–4855
  48. Batist K, Cowan KH, Curt G, Kathi AG. Increased glutathione S-transferase activity (GST) in drug-treated human breast cancer cells. Proc. Am. Assoc. Cancer Res. 1985;26:1362a
  49. Cresteil T, Jaiswal AK. High levels of expression of the NAD(P)H:quinone oxidoreductase (NQO1) gene in tumour cells compared to normal cells of the same origin. Biochem. Pharm. 1991;42:1021–1027
  50. Malkinson AM, Siegel D, Forrest GL, et al.  Elevated DT-diaphorase activity and messanger RNA content in human non-small cell lung carcinomas – relationship to the response of human tumour xenografts to mitomycin C. Cancer Res. 1992;52:4752–4757
  51. Eickelmann P, Ebert T, Warskulat U, Schulz WA, Sies H. Expression of NAD(P)H:quinone oxidoreductase and glutathione S-transferase alpha and pi in human renal cell carcinoma and in kidney cancer-derived cell lines. Carcinogenesis. 1994;15:219–225
  52. Smitskamp-Wilms E, Giaccone G, Pinedo HM, van der Laun BFAM, Peters GJ. DT-diaphorase activity in normal and neoplastic human tissues; an indicator for sensitivity to bioreductive agents. Br. J. Cancer. 1995;72:917–921
  53. Marin A, Lopez de Cerain A, Hamilton E, et al.  DT-diaphorase and cytochrome B5 reductase in human lung and breast tumours. Br. J. Cancer. 1997;76:923–929
  54. Williams JB, Lu AYH, Cameron RG, Pickett CB. 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. 1986;261:5524–5528
  55. Workman P. Enzyme-directed bioreductive drug development revisited: a commentary on recent progress and future prospects with emphasis on quinone anticancer agents and quinone metabolising enzymes, particularly DT-diaphorase. Oncol. Res. 1994;6:461–475
  56. Sistonen L, Holtta E, Makela TP, Keski-Oje J, Alitalo K. The cellular response to induction of the p21 c-Ha-ras oncoprotein includes stimulation of jun gene expression. EMBO. 1989;8:815–822
  57. Mikami K, Naito M, Ishiguro T, et al.  Immunological quantification of DT-diaphorase in carcinoma cell lines and clinical colon cancer cases: advanced tumours express greater levels of DT-diaphorase. Jpn. J. Cancer Res. 1998;89:910–915
  58. Schulz WA, Krummeck A, Rosinger I, et al.  Increased frequency of a null-allele for NAD(P)H:quinone oxidoreductase in patients with urological malignancies. Pharmacogenetics. 1977;7:235–239
  59. Rosvold EA, Mcglynn KA, Lustbader ED, Buetow KH. Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. Pharmacogenetics. 1995;5:199–206
  60. Lafuente MJ, Casterad X, Trias M, et al.  NAD(P)H:quinone oxidoreductase-dependent risk for colorectal cancer and its association with the presence of k-ras mutations in tumours. Carcinogenesis. 2000;21:1813–1819
  61. Zhang J-H, Li Y, Wang R, et al.  NQO1 C609T polymorphism associated with esophageal and gastric cardiac carcinoma in North China. World J. Gastroenterol. 2003;9:1390–1393
  62. Longuemaux S, Delomenie C, Gallon C, et al.  Candidate genetic modifiers of individual susceptibility to renal cell carcinoma: a study of polymorphic human xenobiotic-metabolizing enzymes. Cancer Res. 1999;59:2903–2908
  63. Yin L, Pu Y, Liu T-Y, Tung Y-H, Chen K-W, Lin P. Genetic polymorphisms of NAD(P)H quinone oxidoreductase, CYP1A1 and microsomal epoxide hydrolase and lung cancer risk in Nanjing, China. Lung Cancer. 2001;33:133–141
  64. Hamajima N, Matsuo K, Iwato H, et al.  NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese. Int. J. Clin. Oncol. 2002;7:103–108
  65. Harth V, Donat S, Ko Y, Abel J, Vetter H, Bruning T. NAD(P)H quinone oxidoreductase 1 codon 609 polymorphism and its association to colorectal cancer. Arch. Toxicol. 2000;73:528–531
  66. Peters ES, Kelsey KT, Wiencke JK, et al.  NAT2 and NQO1 polymorphisms are not associated with adult glioma. Cancer Epidemiol. Biomark. Prev. 2001;10:151–152
  67. Soucek P, Sarmanova J, Kristensen VN, Apltauerova M, Gut I. Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin's and non-Hodgkin's lymphomas. Int. Arch. Occup. Environ. Health. 2002;75:S86–S92
  68. Steiner M, Hillenbrand M, Borkowski M, Seiter H, Schuff-Werner P. 609 CàT polymorphism in NAD(P)H:quinone oxidoreductase gene in patients with prostatic adenocarcinoma or benign prostatic hyperplasia. Cancer Lett. 1999;135:67–71
  69. Smith MT, Wang Y, Kane R, et al.  Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukaemia in adults. Blood. 2001;97:1422–1426
  70. Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF. A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with paediatric leukaemias that have MLL fusions. Cancer Res. 1999;59:4095–4099
  71. Krajinovic M, Sinnett H, Richer C, Labuda D, Sinnett D. Role of NQO1, MPO and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukaemia. Int. J. Cancer. 2002;97:230–236
  72. Larson RA, Wang Y, Banerjee M, et al.  Prevalence of the inactivating 609C–>T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Blood. 1999;94:803–807
  73. Blanco JG, Edick MJ, Hancock ML, et al.  Genetic polymorphisms in CYP3A5 CYP3A4 and NQO1 in children who developed therapy-related malignancies. Pharmacogenetics. 2002;12:605–611
  74. Rothman N, Smith MT, Hayes RB, et al.  Benzene poisoning, a risk factor for haematological malignancy, is associated with the NQO1 609C>T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res. 1997;57:2839–2842
  75. Radjendirane V, Joseph P, Lee YH, et al.  Disruption of the DT-diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J. Biol. Chem. 1998;273:7382–7389
  76. Walton MI, Smith PJ, Workman P. The role of NAD(P)H:quinone oxidoreductase (EC 1.6.99.2, DT-diaphorase) in the reductive bioactivation of the novel indoloquinone antitumour agent E09. Cancer Commun. 1991;3:199–206
  77. Pardee AB, Li YZ, Li CJ. Cancer therapy with β-lapachone. Curr. Cancer Drug Targets. 2002;2:227–242
  78. Siegel D, Gibson NW, Preusch PC, Ross D. Metabolism of mitomycin C by DT-diaphorase: role in mitomycin C-induced DNA damage and cytotoxicity in human colon carcinoma cells. Cancer Res. 1990;50:7483–7489
  79. Tudor G, Gutierrez P, Aguilera-Gutierrez A, Sausville EA. Cytotoxicity and apoptosis of benzoquinones: redox cycling, cytochrome release, and BAD protein expression. Biochem. Pharmacol. 2003;65:1061–1075
  80. Nemeikaite-Ceniene A, Sarlauskas J, Anusevicius Z, Nivinskas H, Cenas N. Cytotoxicity of RH1 and related aziridinylbenzoquinones: involvement of activation by NAD(P)H:quinone oxidoreductase (NQO1) and oxidative stress. Arch. Biochem. Biophys. 2003;416:110–118
  81. Hoey BM, Butler JB, Swallow AJ. Reductive activation of mitomycin C. Biochemistry. 1988;27:2608–2614
  82. Fitzsimmons SA, Workman P, Grever M, Paull K, Camalier R, Lewis AD. Reductase enzyme expression across the national cancer institute tumour cell line panel: correlation with sensitivity to mitomycin C and E09. J. Natl. Cancer Inst. 1996;83:259–269
  83. Gustafson DL, Beal HD, Bolton EM, Ross D, Waldren CA. Expression of human NAD(P)H: quinone oxoreductase (DT-diaphorase) in chinese hamster ovary cells; effects on the cytotoxicity of antitumour quinones. Mol. Pharmacol. 1996;50:728–735
  84. Nishiyama M, Saeki S, Aogi K, Hirabayashi N, Toge T. Relevance of DT-diaphorase activity to mitomycin C efficacy on human cancer cells: differences in in vitro and in vivo systems. Int. J. Cancer. 1993;53:1013–1016
  85. Phillips RM, Burger AM, Loadman PM, Jarrett CM, Swaine DJ, Fiebig H-H. Predicting tumour responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumour homogenates: implications for enzyme-directed bioreductive drug development. Cancer Res. 2000;60:6384–6390
  86. Marshall RS, Paterson MC, Rauth AM. DT-diaphorase activity and mitomycin C sensitivity in non-transformed cell strains derived from members of a cancer-prone family. Biochem. Pharmacol. 1991;12:1175–1180
  87. Beall HD, Murphy AM, Siegel D, Hargreaves RH, Butler J, Ross D. Nicotinamide adenine dinucleotide (Phosphate):quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumour quinones; quinone cytotoxicity and selectivity in human lung and breast cancer cell lines. Mol. Pharmacol. 1995;48:499–504
  88. Siegel D, Beall H, Kasai M, Atal H, Gibson NW, Ross D. pH-dependent inactivation of DT-diaphorase by mitomycin C and porfiromycin. Mol. Pharmacol. 1993;44:1128–1134
  89. Robertson N, Stratford IJ, Houlbrook S, Carmichael J, Adams GE. The sensitivity of human tumour cells to quinone bioreductive drugs: what role for DT-diaphorase. Biochem. Pharm. 1992;44:409–412
  90. Schellens JHM, Planting AS, van Acker BAC, et al.  Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09. J. Natl. Cancer Inst. 1994;86:906–912
  91. Knox RJ, Friedlos F, Jarman M, Roberts JJ. A new cytotoxic DNA interstrand crosslinking agent 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide is formed from 5-(aziridin-1-yl-2,4-dinitrobenzamide (CB1954) by a nitroreductase enzyme in walker carcinoma cells. Biochem. Pharmacol. 1988;37:4661–4669
  92. Boland MP, Knox RJ, Roberts JJ. The differences in kinetics of rat and human DT-diaphorase result in a differential sensitivity of derived cell lines to CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide). Biochem. Pharmacol. 1991;41:867–875
  93. Knox RJ, Jenkins TC, Hobbs SM, Chen S, Melton RG, Burke PJ. Bioactivation of 5-(aziridin–yl)-2,4-dinitrobenzamide (CB1954) by human NAD(P)H:quinone oxidoreductase. 2. A novel co-substrate-mediated antitumour prodrug therapy. Cancer Res. 2000;60:4179–4186
  94. Butler J, Dzielendziak A, Lea JS, Ward TH, Hoey BM. Contrasting cytotoxic mechanisms of similar antitumour diaziridinylbenzoquinones. Free Rad. Res. Comms. 1990;8:231–239
  95. Gibson NW, Hartley JA, Butler J, Siegel D, Ross D. Relationship between DT-diaphorase mediated metabolism of a series of aziridinylbenzoquinones and DNA damage and cytotoxicity. Mol. Pharmacol. 1992;42:531–536
  96. Haid M, Khandekhar JD, Christ M, et al.  Aziridinylbenzoquinone in recurrent, progressive glioma of the central nervous system. A Phase II study by the Illinois Cancer Council. Cancer. 1985;56:1311–1315
  97. Case DC, Hayes DM. Phase II study of aziridinylbenzoquinone in refractory lymphoma. Cancer Treat Rep. 1983;67:993–996
  98. Lee CS, Hartley JA, Beradini MD, et al.  Alteration in DNA cross-linking and sequence selectivity of a series of aziridinylbenzoquinones after enzymatic reduction by DT-diaphorase. Biochemistry. 1992;31:3019–3025
  99. Berardini MD, Souhami RL, Lee CS, Gibson NW, Butler J, Hartley JA. Two structurally related diaziridinylbenzoquinones preferentially cross-link DNA at different sites upon reduction with DT-diaphorase. Biochemistry. 1993;32:3306–3312
  100. Naylor MA, Swann E, Everett J, et al.  Indolequinone antitumor agents: reductive activation and elimination from (5-methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl derivatives and hypoxia-selective cytotoxicity in vitro. J. Med. Chem. 1998;41:2720–2731
  101. Xing C, Skibo EB. Sigmatropic reactions of the aziridinyl semiquinone species. Why aziridinyl benzoquinones are metabolically more stable than aziridinyl indoloquinones. Biochemistry. 2000;39:10770–10780
  102. Loadman PM, Phillips RM, Lim LE, Bibby MC. Pharmaocological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxyl)-6-methyl-1,4-benzoquinone) in mice. Biochem. Pharmacol. 2000;59:831–837
  103. Winski SL, Hargreaves RH, Butler J, Ross D. A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumour quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumour agent. Clin. Cancer Res. 1998;4:3083–3088
  104. Sausville E. NCI developmental therapeutics program (personal communication)
  105. Hollander PM, Ernster L. Studies on the reaction mechanism of DT diaphorase. Action of dead-end inhibitors and effects of phospholipids. Arch. Biochem. Biophys. 1975;169:560–567
  106. Chen S, Wu K, Zhang D, Sherman M, Knox R, Yang CS. Molecular characterisation of binding of substrates and inhibitors to DT-diaphorase: combined approach involving site-directed mutagenesis, inhibitor-binding analysis and computer modelling. Mol. Pharmacol. 1999;56:272–278
  107. Winski SL, Faig M, Bianchet MA, et al.  Characterization of a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1 by biochemical, X-ray crystallographic and mass spectrometric approaches. Biochemistry. 2001;40:15135–15142
  108. Begleiter A, Leith MK, Curphey TJ. Induction of DT-diaphorase by 1,2-dithiole-3-thione and increase of anticancer activity of bioreductive agents. Br. J. Cancer. 1996;27:S9–S14
  109. Twerdok LE, Rembish SJ, Trush MA. Induction of quinone reductase and glutathione in bone marrow cells by 1,2-dithiole-3-thione: effect on hydroquinone-induced cytotoxicity. Toxicol. Appl. Pharmacol. 1992;112:273–281
  110. Li Y, Lafuente A, Trush MA. Characterisation of quinone oxidoreductase, glutathione and glutathione S-transferase in human myeloid cell lines: induction by 1,2-dithiole-3-thione and effects on hydroquinone-induced cytotoxicity. Life Sci. 1994;54:901–916
  111. Doherty GP, Leith MK, Wang X, Curphey TJ, Begleiter A. Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents. Br. J. Cancer. 1998;77:1241–1252
  112. Begleiter A, Leith MK, Doherty GP, Digby TJ, Pan S. Factors influencing the induction of DT-diaphorase activity by 1,2-dithiole-3-thione in human tumour cell lines. Biochem. Pharmacol. 2001;61:955–964
  113. Wang X, Doherty GP, Leith MK, Curphey TJ, Begleiter A. Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase. Br. J. Cancer. 1999;80:1223–1230
  114. Carr BA, Franklin MR. Induction of drug metabolising enzymes by 1,7-phenanthroline and oltipraz in mice is unrelated to Ah-responsiveness. J. Biochem. Toxicol. 1999;13:77–82
  115. Kensler TW, Egner PA, Dolan PM, Groopman JD, Roebuck BD. Mechanism of protection against aflatoxin tumourigenecity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones. Cancer Res. 1987;47:4271–4277
  116. O'Dwyer PJ, Clayton M, Halbherr T, Myers CB, Yao K. Cellular kinetics of induction by oltipraz and its keto derivative of detoxification enzymes in human colon adenocarcinoma cells. Clin. Cancer Res. 1997;3:783–791
  117. Jiang Z-Q, Chen C, Yang B, Habbar V, Kong A-NT. Differential responses from seven mammalian cell lines to the treatments of detoxifying enzyme inducers. Life Sci. 2003;72:2243–2253
  118. Gordon GB, Prochaska HJ, Yang LY-S. Induction of NAD(P)H:quinone reductase in human peripheral blood lymphocytes. Carcinogenesis. 1991;12:2393–2396
  119. Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. PNAS. 1992;89:2399–2403
  120. Flescher E, Snyder CA. Aspirin-like drugs can protect human T lymphocytes against benzoquinone cytotoxicity. Arch. Toxicol. 1995;69:684–689
  121. Hou D-X, Fukuda M, Johnson JA, Miyamori K, Ushikai M, Fujii M. Fisetin induces transcription of NADPH:quinone oxidoreductase gene through an antioxidant responsive element-involved activation. Int. J. Oncol. 2001;18:1175–1179
  122. Heo YH, Kim S, Park JE, Jeong LS, Lee SK. Induction of quinone reductase activity by stilbene analogs in mouse Hepa 1c1c7 cells. Arch. Pharm. Res. 2001;24:597–600
  123. Valerio LG, Kepa JK, Pickwell GV, Quattrochi LC. Induction of human NAD(P)H:quinone oxidoreductase (NQO1) gene expression by the flavenol quercetin. Toxicol. Lett. 2001;119:49–57
  124. McMahon M, Itoh K, Yamamoto M, et al.  The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 2001;61:3299–3307
  125. Begleiter A, Leith MK. Induction of DT-diaphorase by doxorubicin and combination therapy with mitomycin C in vitro. Biochem. Pharmacol. 1995;50:1281–1286
  126. Gonzalez S, Labombarda F, Deniselle MCG, Saravia FE, Roig P, De Nicola AF. Glucocorticoid effects on fos immunoreactivity and NADPH-diaphorase histochemical staining following spinal cord injury. Brain Res. 2001;912:144–153
  127. Yao KS, Clayton M, O'Dwyer PJ. Interaction of heat and hypoxia in modulating transcription of DT diaphorase in human colon adenocarcinoma cells. Cell Growth Differ. 1994;5:125–131
  128. Alvarez S, Boveria A. Induction of antioxidant enzymes and DT-diaphorase in human blood mononuclear cells by light stress. Arch. Biochem. Biophy. 1993;305:247–251
  129. Kolesar J, Miller J, Duan W, et al.  T1 induction in PBMC by mitomycin C predicts response to irinotecan. Proc. ASCO. 2002;22:456a
  130. Begleiter A, Leith MK, Curphey TJ, Doherty GP. Induction of DT-diaphorase in cancer chemoprevention and chemotherapy. Oncol. Res. 1997;9:371–382
  131. Kepa JK, Ross D. DT-diaphorase activity in NSCLC and SCLC cell lines: a role for fos/jun regulation. Br. J. Cancer. 1999;79:1679–1684
  132. Yu R, Lei W, Mandlekar S, et al.  Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J. Biol. Chem. 1999;274:27545–27552
  133. Watternberg LW, Bueding E. Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (Oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethylnitrosamine and uracil mustard. Carcinogenesis. 1986;7:1379–1381
  134. Egner PA, Kensler TW, Prestera T, et al.  Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones. Carcinogenesis. 1994;15:177–181
  135. Szarka CE, Yao KS, Pfeiffer GR, et al.  Chronic dosing of oltipraz in people at increased risk for colorectal cancer. Cancer Detect Prev. 2001;25:352–361
  136. Morrow CS, Cowan KH. Mechanisms and clinical significance of multidrug resistance. Oncology. 1988;2:55–63
  137. Mikami K, Naito M, Tomida A, Yamada M, Sirakusa T, Tsuruo T. DT-diaphorase as a critical determinant of sensitivity to mitomycin C in human colon and gastric carcinoma cell lines. Cancer Res. 1996;56:2823–2826
  138. Sagara N, Katoh M. Mitomycin C resistance is induced by TCF-3 overexpression in gastric cancer cell line MKN28 is associated with DT-diaphorase down-regulation. Cancer Res. 2000;60:5959–5962
  139. Lambert PA, Kang Y, Greaves B, Perry RR. The importance of DT-diaphorase in mitomycin C resistance in human colon cancer cell lines. J. Surg. Res. 1998;80:177–181
  140. Singh SV, Scalamogna D, Xia H, et al.  Biochemical characterisation of a mitomycin C resistant human bladder cancer cell line. Int. J. Cancer. 1996;65:852–857
  141. Baumann P, Hodnick WF, Scow HA, et al.  Reversal of mitomycin C resistance by overexpression of bioreductive enzymes in Chinese hamster ovary cells. Cancer Res. 2001;61:7770–7776
  142. O'Dwyer PJ, Perez RP, Yao KS, Godwin AK, Hamilton TC. Increased DT-diaphorase expression and cross-resistance to mtomycin C in a series of cisplatin-resistant human ovarian cancer cell lines. Biochem. Pharmacol. 1996;52:21–27
  143. Wakusawa S, Nalamura S, Miyamoto K. Establishment by adriamycin exposure of multidrug-resistant rat ascites hepatoma AH130 cells showing low DT-diaphorase activity and high cross resistance to mitomycins. Jpn. J. Cancer Res. 1997;88:88–96
  144. Ward TH, Haran MS, Whittaker D, Watson AJ, Howard TD, Butler J. Cross-resistance studies on two K562 sublines resistant to diaziridinylbenzoquinones. Biochem. Pharmacol. 1995;50:459–464
  145. Danson S, Ranson M, Denneny O, Jones N, Ward TH. Drug resistance studies on two paired cell lines resistant to the diaziridinylbenzoquinone, RH1. British Oncological Association Annual Meeting, 2003

PII: S0305-7372(04)00026-X

doi: 10.1016/j.ctrv.2004.01.002

Cancer Treatment Reviews
Volume 30, Issue 5 , Pages 437-449 , August 2004

Article Tools

* Image Usage & Resolution