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

• Dicumarol is a naturally occurring anticoagulant derived from coumarin that induces cytotoxicity and oxidative stress in human pancreatic cancer cells (Cullen, J. J., Hinkhouse, M. M., Grady, M., Gaut, A. W., Liu, J., Zhang, Y., Weydert, C. J. D., Domann, F. E., and Oberley, L. W. (2003) Cancer Res. 63, 5513-5520) [11].
• The greatest mitochondrial drug metabolism was achieved in the presence of NADPH as cofactor and hypoxia (MAC 16-specific activity, 3.67 +/- 0.58 nmol/30 min/mg; MAC 26 specific-activity, 3.87 +/- 0.71 nmol/30 min/mg) and was unaffected by the addition of the inhibitors dicoumarol and cytochrome P-450 reductase antiserum [12].
• Synergistic cytotoxicity between menadione and dicumarol vs. murine leukemia L1210 [13].
• At 30 microM dicumarol, an inhibitor of quinone reductase, potentiated the acute toxicity of quinoneimines to cultured phenobarbital-induced rat hepatocytes by 0.7- to 2.9-fold [14].
• The HT-29 cell line was only vulnerable to NQ and MEN after inhibition of DT-diaphorase (DTD) with dicoumarol, whereas dicoumarol did not affect the toxicity of quinones to Caco-2 cells [15].

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

• Metabolism of mitomycin C by HT-29 cytosol was inhibited by prior boiling of cytosol or by the inclusion of dicoumarol [19].
• Both mitomycin C-induced cytotoxicity and induction of DNA interstrand cross-links could be inhibited by pretreatment of HT-29 cells with dicoumarol [19].
• Dicoumarol: a unique microtubule stabilizing natural product that is synergistic with Taxol [20].
• In the breast carcinoma cell line MCF-7, treatment with dicumarol also induced apoptosis [16].
• Dicumarol with the mitochondrial electron transport chain blocker antimycin A decreased clonogenic survival and increased superoxide levels in cells with functional mitochondria but had little effect on cancer cells without functional mitochondria [11].

Associations of dicoumarin with other chemical compounds

• Recombinant human QR2: (i) reacts with N-ribosyl- and N-alkyldihydronicotinamides, but not with NADH, NADPH, or NMNH; (ii) is very weakly inhibited by dicumarol or Cibacron blue; (iii) is very potently inhibited by benzo[a]pyrene [21].
• Activation of ERK 1/2 was demonstrated to be independent of NAD(P)H:quinone oxidoreductase using the inhibitor dicoumarol, thus excluding redox cycling as the major mechanism causing these menadione effects [22].
• Reduction of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone; AZQ) by purified rat hepatic DT-diaphorase was NADH and enzyme dependent and was inhibited by prior boiling of the enzyme or by dicumarol [23].
• Although dicumarol has been used as an inhibitor of the two-electron reductase NAD(P)H:quinone oxidoreductase (NQO1), dicumarol is also thought to affect quinone-mediated electron transfer reactions in the mitochondria, leading to the production of superoxide (O(2)(.)) and hydrogen peroxide (H(2)O(2)) [11].
• Site-directed mutagenesis was utilized to identify binding sites for NAD(P)H and dicumarol in rat liver NAD(P)H:quinone oxidoreductase (NQOR, EC 1.6.99.2) [24].

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