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Chemical Compound Review

dicumarol     2-hydroxy-3-[(2-hydroxy-4- oxo-chromen-3...

Synonyms:
 
 
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Disease relevance of dicoumarin

  • The tumor suppressor p14(ARF) and the viral oncogenes SV40 LT and adenovirus E1A that are known to stabilize p53 inhibited dicoumarol-induced p53 degradation [1].
  • Dicoumarol-induced degradation of p53 also was prevented in the presence of simian virus 40 large T antigen, which is known to bind and to stabilize p53 [2].
  • These findings suggested that dicoumarol might enhance the toxicity of MC to the hypoxic cells of solid tumors, without increasing the toxic side effects of the antibiotic to the host [3].
  • Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism [4].
  • Adducts of mitomycin C and DNA in EMT6 mouse mammary tumor cells: effects of hypoxia and dicumarol on adduct patterns [5].
 

Psychiatry related information on dicoumarin

  • In motor activity and rearing behavior, the simultaneous injection of Mn(3+) plus dicumarol produced a 6-OHDA-like impairment [6].
 

High impact information on dicoumarin

  • We show that these microspheres increase the absorption of three model substances of widely different molecular size: dicumarol, insulin and plasmid DNA [7].
  • We further show that dicoumarol sensitizes ODC monomers to proteasomal degradation in an antizyme-independent manner [8].
  • Neither dicoumarol nor curcumin dissociated the complexes of NQO1 and the human cancer hot-spot p53 R273H mutant and therefore did not induce degradation of this mutant [9].
  • The NQO1 inhibitor dicoumarol induces ubiquitin-independent p53 degradation [10].
  • In vitro studies indicate that dicoumarol-induced p53 degradation was ubiquitin-independent and ATP-dependent [1].
 

Chemical compound and disease context of dicoumarin

 

Biological context of dicoumarin

  • Dicumarol also inhibited cell growth, plating efficiency, and growth in soft agar [4].
  • To determine whether inhibition of NQO(1) would alter the malignant phenotype, MIA PaCa-2 pancreatic cancer cells were treated with a selective inhibitor of NQO(1), dicumarol [4].
  • Transient activation of Jun N-terminal kinases and protection from apoptosis by the insulin-like growth factor I receptor can be suppressed by dicumarol [16].
  • The kinetics of activation of normal and gamma-carboxyglutamic acid (Gla)-deficient prothrombins isolated from cattle maintained for extended periods on the vitamin K antagonist dicoumarol were studied [17].
  • Synthesis of the photoaffinity probe 3-(p-azidobenzyl)-4-hydroxycoumarin and identification of the dicoumarol binding site in rat liver NAD(P)H:quinone reductase (EC 1.6.99.2) [18].
 

Anatomical context of dicoumarin

 

Associations of dicoumarin with other chemical compounds

 

Gene context of dicoumarin

  • Further mutational analysis showed that arginines at positions 175 and 248 were essential for dicoumarol-induced p53 degradation [10].
  • Inhibition of NQO1 activity by dicoumarol induces p53 and p73 proteasomal degradation [1].
  • Pretreatment of K562 cells with the JNK inhibitor, dicoumarol, abolished PBOX-6-induced phosphorylation of c-Jun and ATF-2 and inhibited the induced apoptosis, suggesting that JNK activation is an essential component of the apoptotic pathway induced by PBOX-6 [25].
  • A mutant p53 (p53([22,23])), which is resistant to Mdm-2-mediated degradation, was susceptible to dicoumarol-induced degradation [1].
  • Photoaffinity labeling and protection experiments carried out on purified preparations of L-FABP paralleled the labeling results obtained in the microsomes and cytosol, confirming that L-FABP is capable of specifically binding AzBHC, warfarin, and dicoumarol [26].
 

Analytical, diagnostic and therapeutic context of dicoumarin

  • The high performance liquid chromatography techniques were also used to examine the effects of dicumarol (DIC) on adduct patterns in cells treated simultaneously with 3H-MC [5].
  • In contrast with other human diaphorases, it is dependent on FAD for activity after electrophoresis, inhibited by low concentrations of dicoumarol and shows a marked affinity for Cibacron Blue. The molecular weight was estimated to be 49000 +/- 1800 by gel filtration [27].
  • Moreover, a non-toxic DTD inhibitor, dicoumarol (DIC), or flavin adenine dinucleotide (FAD), suppressed the efficacy of MMC in culture cells, but enhanced it in xenografts [28].
  • In search for specific circular dichroism (CD) probes, dicumarol and acridine orange were found to specifically bind to the F1-S and A variants, respectively [29].
  • Drug metabolism was assayed spectrophotometrically or by HPLC, with dicoumarol as a selective inhibitor [30].

References

  1. Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Asher, G., Lotem, J., Sachs, L., Kahana, C., Shaul, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Asher, G., Lotem, J., Cohen, B., Sachs, L., Shaul, Y. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Enhancement of mitomycin C cytotoxicity to hypoxic tumor cells by dicoumarol in vivo and in vitro. Keyes, S.R., Rockwell, S., Sartorelli, A.C. Cancer Res. (1985) [Pubmed]
  4. Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism. Cullen, J.J., Hinkhouse, M.M., Grady, M., Gaut, A.W., Liu, J., Zhang, Y.P., Weydert, C.J., Domann, F.E., Oberley, L.W. Cancer Res. (2003) [Pubmed]
  5. Adducts of mitomycin C and DNA in EMT6 mouse mammary tumor cells: effects of hypoxia and dicumarol on adduct patterns. Bizanek, R., Chowdary, D., Arai, H., Kasai, M., Hughes, C.S., Sartorelli, A.C., Rockwell, S., Tomasz, M. Cancer Res. (1993) [Pubmed]
  6. Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor. Díaz-Véliz, G., Mora, S., Gómez, P., Dossi, M.T., Montiel, J., Arriagada, C., Aboitiz, F., Segura-Aguilar, J. Pharmacol. Biochem. Behav. (2004) [Pubmed]
  7. Biologically erodable microspheres as potential oral drug delivery systems. Mathiowitz, E., Jacob, J.S., Jong, Y.S., Carino, G.P., Chickering, D.E., Chaturvedi, P., Santos, C.A., Vijayaraghavan, K., Montgomery, S., Bassett, M., Morrell, C. Nature (1997) [Pubmed]
  8. 20S proteasomal degradation of ornithine decarboxylase is regulated by NQO1. Asher, G., Bercovich, Z., Tsvetkov, P., Shaul, Y., Kahana, C. Mol. Cell (2005) [Pubmed]
  9. Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin. Tsvetkov, P., Asher, G., Reiss, V., Shaul, Y., Sachs, L., Lotem, J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. P53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1. Asher, G., Lotem, J., Tsvetkov, P., Reiss, V., Sachs, L., Shaul, Y. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  11. Mitochondrial Production of Reactive Oxygen Species Mediate Dicumarol-induced Cytotoxicity in Cancer Cells. Du, J., Daniels, D.H., Asbury, C., Venkataraman, S., Liu, J., Spitz, D.R., Oberley, L.W., Cullen, J.J. J. Biol. Chem. (2006) [Pubmed]
  12. Enzymology of mitomycin C metabolic activation in tumour tissue. Characterization of a novel mitochondrial reductase. Spanswick, V.J., Cummings, J., Smyth, J.F. Biochem. Pharmacol. (1996) [Pubmed]
  13. Synergistic cytotoxicity between menadione and dicumarol vs. murine leukemia L1210. Akman, S.A., Doroshow, J.H., Dietrich, M.F., Chlebowski, R.T., Block, J.S. J. Pharmacol. Exp. Ther. (1987) [Pubmed]
  14. Quinoneimines as substrates for quinone reductase (NAD(P)H: (quinone-acceptor)oxidoreductase) and the effect of dicumarol on their cytotoxicity. Powis, G., See, K.L., Santone, K.S., Melder, D.C., Hodnett, E.M. Biochem. Pharmacol. (1987) [Pubmed]
  15. Quinone toxicity in DT-diaphorase-efficient and -deficient colon carcinoma cell lines. Karczewski, J.M., Peters, J.G., Noordhoek, J. Biochem. Pharmacol. (1999) [Pubmed]
  16. Transient activation of Jun N-terminal kinases and protection from apoptosis by the insulin-like growth factor I receptor can be suppressed by dicumarol. Krause, D., Lyons, A., Fennelly, C., O'Connor, R. J. Biol. Chem. (2001) [Pubmed]
  17. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. Malhotra, O.P., Nesheim, M.E., Mann, K.G. J. Biol. Chem. (1985) [Pubmed]
  18. Synthesis of the photoaffinity probe 3-(p-azidobenzyl)-4-hydroxycoumarin and identification of the dicoumarol binding site in rat liver NAD(P)H:quinone reductase (EC 1.6.99.2). Myszka, D.G., Swenson, R.P. J. Biol. Chem. (1991) [Pubmed]
  19. Metabolism of mitomycin C by DT-diaphorase: role in mitomycin C-induced DNA damage and cytotoxicity in human colon carcinoma cells. Siegel, D., Gibson, N.W., Preusch, P.C., Ross, D. Cancer Res. (1990) [Pubmed]
  20. Dicoumarol: a unique microtubule stabilizing natural product that is synergistic with Taxol. Madari, H., Panda, D., Wilson, L., Jacobs, R.S. Cancer Res. (2003) [Pubmed]
  21. Unexpected genetic and structural relationships of a long-forgotten flavoenzyme to NAD(P)H:quinone reductase (DT-diaphorase). Zhao, Q., Yang, X.L., Holtzclaw, W.D., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  22. 2-Methyl-1,4-naphthoquinone, vitamin K(3), decreases gap-junctional intercellular communication via activation of the epidermal growth factor receptor/extracellular signal-regulated kinase cascade. Klotz, L.O., Patak, P., Ale-Agha, N., Buchczyk, D.P., Abdelmohsen, K., Gerber, P.A., von Montfort, C., Sies, H. Cancer Res. (2002) [Pubmed]
  23. Metabolism of diaziquone by NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase): role in diaziquone-induced DNA damage and cytotoxicity in human colon carcinoma cells. Siegel, D., Gibson, N.W., Preusch, P.C., Ross, D. Cancer Res. (1990) [Pubmed]
  24. Identification of a glycine-rich sequence as an NAD(P)H-binding site and tyrosine 128 as a dicumarol-binding site in rat liver NAD(P)H:quinone oxidoreductase by site-directed mutagenesis. Ma, Q., Cui, K., Xiao, F., Lu, A.Y., Yang, C.S. J. Biol. Chem. (1992) [Pubmed]
  25. Activation of the c-Jun N-terminal kinase (JNK) signaling pathway is essential during PBOX-6-induced apoptosis in chronic myelogenous leukemia (CML) cells. Mc Gee, M.M., Campiani, G., Ramunno, A., Nacci, V., Lawler, M., Williams, D.C., Zisterer, D.M. J. Biol. Chem. (2002) [Pubmed]
  26. Identification by photoaffinity labeling of fatty acid-binding protein as a potential warfarin receptor in rat liver. Myszka, D.G., Swenson, R.P. J. Biol. Chem. (1991) [Pubmed]
  27. Human FAD-dependent NAD(P)H diaphorase. Edwards, Y.H., Potter, J., Hopkinson, D.A. Biochem. J. (1980) [Pubmed]
  28. Relevance of DT-diaphorase activity to mitomycin C (MMC) efficacy on human cancer cells: differences in in vitro and in vivo systems. Nishiyama, M., Saeki, S., Aogi, K., Hirabayashi, N., Toge, T. Int. J. Cancer (1993) [Pubmed]
  29. Specific ligand binding on genetic variants of human alpha1-acid glycoprotein studied by circular dichroism spectroscopy. Fitos, I., Visy, J., Zsila, F., Bikádi, Z., Mády, G., Simonyi, M. Biochem. Pharmacol. (2004) [Pubmed]
  30. The role of human and rodent DT-diaphorase in the reductive metabolism of hypoxic cell cytotoxins. Walton, M.I., Sugget, N., Workman, P. Int. J. Radiat. Oncol. Biol. Phys. (1992) [Pubmed]
 
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