Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of oxidative stress induced by redox-enzyme modulation on the progression stage of hepatocarcinogenesis were examined by monitoring both hepatocyte injury and hepatocellular carcinoma development in F344 rats bearing preneoplastic liver nodules induced by the Cayama-Farber procedure. Redox-enzyme modulation, which included increased cytochrome P450 reductase activity induced by phenobarbital-Na (100 mg/kg, i.p. for 3 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.), depletion of glutathione by phorone (200 mg/kg, i.p.), supplementation with the Fe(III) sodium salt of EDTA (50 mg/kg, i.p.) and redox-cycling activation by menadione (50 mg/kg, i.g.), exerted no prominent hepatocyte injury within nodules but did cause slight injury in the surrounding hepatocytes in nodule-bearing rats. The same treatments induced severe hepatocyte injury in non-treated normal rats. Redox-enzyme modulation performed every other week for 33 weeks significantly reduced the number of hepatocellular carcinomas developing in nodule-bearing rats. These results indicate that preneoplastic nodules are resistant to the oxidative stress induction caused by redox-enzyme modulation treatment and that, despite toxic effects in surrounding hepatocytes, no progression pressure is exerted. Indeed, the treatment rather demonstrates an inhibitory effect of the evolution of the nodules into hepatocellular carcinomas.
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PMID:Effects of oxidative stress induced by redox-enzyme modulation on the progression stage of rat hepatocarcinogenesis. 842 75

We studied a selective enhancement of the mitomycin C (MMC)-induced antitumor effect focusing on the intracellular metabolism by NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD). The level of cellular DTD activity related well to the degree of MMC-induced DNA total cross links and cell growth inhibition in human cancer cell lines, KB, PH101, SH101 and K562. A DTD inhibitor, dicoumarol (DIC) or flavin adenine dinucleotide (FAD), inhibited the MMC-induced DNA damage and cytotoxicity at a non-toxic concentration. The DTD-mediated MMC activation was pH-dependent, and highest at pH 6 and lowest at pH 8. Although an inverse relationship appeared to exist between DTD activity and MMC efficacy in human xenografts implanted into nude mice and 9 fresh human tumor specimens, the investigation in 3 culture cells, HEC-46, HCC-48 and HCC-50, established from those xenografts, showed that DTD activated MMC in a pH-dependent manner as well as the other cell lines. Significant tumor pH reduction from 7.1 to 6.7 by continuous glucose infusion also increased the MMC-induced tumor growth inhibition in the human tumor xenografts. Thus, we conclude that bioreductive activation by DTD in a pH-dependent manner may be of key importance in the MMC-induced antitumor effect and that an increased MMC efficacy at a reduced pH caused by hyperglycemia may be applied to clinical use as a new manipulation for a biochemical modulation of MMC.
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PMID:DT-diaphorase as a target enzyme for biochemical modulation of mitomycin C. 856 14

We have studied the response of genes in the dioxin-inducible [Ah] battery to three compounds that protect mouse hepatoma cells (Hepa-1c7c7 wild-type, wt) against menadione toxicity. Pretreatment of wt cells with 25 microM 5,10-dihydroindenol[1,2-b]indole (DHII), 25 microM tert-butylhydroquinone (tBHO) or 10 microM menadione itself, generated substantial protection against toxicity produced by subsequent menadione exposure. The gene response was examined in wt cells, and three mutant lines: CYP1A1 metabolism-deficient (c37 or P1-); nuclear translocation-impaired (c4 or nt-); and AHR-deficient (c2 or r-, containing < 10% of normal functional receptor levels). DHII treatment of wt cells for 12 hr markedly elevated the enzyme activities and mRNA levels of genes in the [Ah] battery: aryl hydrocarbon hydroxylase (Cyp1a1), NAD(P)H:menadione oxidoreductase (Nmol), cytosolic aldehyde dehydrogenase class 3 (Ahd4), and UDP-glucuronosyltransferase form 1*06 (Ugt1*06). Treatment of the c4 and c2 cells with DHII failed to induce mRNA levels of the genes, indicating that induction of the [Ah] gene battery by DHII is aromatic hydrocarbon receptor (AHR)-mediated. On the other hand, neither tBHO nor menadione caused increases in CYPlAl mRNA, but tBHQ significantly enhanced the NMO1, AHD4, and UGT1*06 mRNA levels in all three mutant cell lines. In conclusion, we expect one or more putative electrophile response elements (EpRE), previously found in the regulatory regions of the murine Nmol, Ahd4, and ugt1*06 genes, to be functional in responding to phenolic antioxidants.
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PMID:Response of [Ah] battery genes to compounds that protect against menadione toxicity. 861 69

A resistant subline (AH130/5A) selected from rat hepatoma AH130 cells after exposure to adriamycin (ADM) showed remarkable resistance to multiple antitumor drugs, including mitomycin C (MMC) and porfiromycin (PFM). PFM, vinblastine (VLB), and ADM accumulated in AH130/5A far less than in the parent AH130 (AH130/P) cells. AH130/5A cells showed overexpression of P-glycoprotein (PGP), an increase in glutathione S-transferase activity, and a decrease in DT-diaphorase and glutathione peroxidase activity. The resistance to MMC and VLB of AH130/5A cells was partly reversed by H-87, an inhibitor of PGP. Buthionine sulfoximine, an inhibitor of glutathione synthase, did not affect the action of MMC. tert-Butylhydroquinone induced DT-diaphorase activity, increased PFM uptake, and enhanced the growth-inhibitory action of MMC in AH130/5A cells. Dicumarol, an inhibitor of DT-diaphorase, decreased PFM uptake and reduced the growth-inhibitory action of MMC in AH130/P cells. These results indicated that the adriamycin treatment of hepatoma cells caused multifactorial multidrug resistance involving a decrease in DT-diaphorase activity.
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PMID:Establishment by adriamycin exposure of multidrug-resistant rat ascites hepatoma AH130 cells showing low DT-diaphorase activity and high cross resistance to mitomycins. 904 1

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and wine. It has antioxidant and antiproliferative activities, and has been shown to induce NAD(P)H:quinone oxidoreductase, also known as DT-diaphorase, in cultured mouse hepatoma cells. DT-diaphorase is a detoxifying enzyme for quinone-containing substances, due to its ability to prevent their one-electron reduction and the consequent generation of reactive oxygen species (ROS). The aim of the present study was to investigate whether oral administration of trans-resveratrol to guinea pigs (60 mg/l in tap water for 16 days, ad libitum) increases cardiac DT-diaphorase and, consequently, reduces the response of isolated atria to 2-methyl-1,4-naphthoquinone (menadione), the positive inotropic effect of which is related to the amount of ROS generated by its cardiac metabolism. In the cardiac tissue of resveratrol-treated animals, DT-diaphorase activity was significantly higher than that measured in control animals, the V(max) of the enzyme reaction being 75.47 +/- 3.87 and 50.73 +/- 0.63 nmoles/mg protein/min, respectively (p < 0.05). Resveratrol administration also significantly increased the activity of cardiac catalase (32.20 +/- 2.39 vs. 25.14 +/- 3.85 units/mg protein in treated and control animals, respectively; p < 0.001). As a consequence, menadione metabolism by the cardiac homogenate obtained from resveratrol-treated animals generated a smaller amount of ROS and, in electrically driven left atria, menadione produced a significantly lower increase in the force of contraction than in atria isolated from control animals. These results indicate that oral administration of resveratrol exerts cardioprotection against ROS-mediated menadione toxicity.
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PMID:Oral administration of trans-resveratrol to guinea pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atria from menadione toxicity. 1267 91

Primary cultures of human hepatocytes and hepatoma cell line HepG2 are frequently used to evaluate the hepatic disposition of drugs and other xenobiotics. To check the variability of the expression of drug-metabolizing enzymes in these in vitro models, expression of genes coding for several cytochrome P450 isoforms and phase II enzymes was quantified during culture time by real-time RT-PCR. Gene expression was determined daily for primary hepatocytes maintained in a sandwich culture over 1 week and for HepG2, during the first 10 passages. In primary hepatocytes characteristic expression trends were observed which could be abstracted into three major classes of time curves. Genes of the first and the second class had an expression maximum around day 6 and day 4 in culture, respectively. The third class of genes had two expression peaks: at day 1 and 5 in culture. Surprisingly, also the cell line HepG2 showed significant expression changes during passages. For example, gene expression of cytochrome 1A1 varied 8-fold, that of cytochrome 2B6 30-fold, and that of NADP-quinone reductase 1 more than 200-fold within the first 10 passages. In conclusion, neither primary hepatocytes nor HepG2 cell line display a model for constant expression of drug-metabolizing enzymes.
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PMID:Influence of culture time on the expression of drug-metabolizing enzymes in primary human hepatocytes and hepatoma cell line HepG2. 1289 44

TCDD (2,3,7,8-tetrachlorodibenzo- p -dixoin) induces phase II drug-metabolizing enzyme NQO1 [NAD(P)H:quinone oxidoreductase; EC 1.6.99.2; DT-diaphorase] in a wide range of mammalian tissues and cells. Here, we analysed the molecular pathway mediating NQO1 induction by TCDD in mouse hepatoma cells. Inhibition of protein synthesis with CHX (cycloheximide) completely blocks induction of NQO1 by TCDD as well as the basal expression and induction by phenolic antioxidant tBHQ (2-t-butylbenzene-1,4-diol), implicating a labile factor in NQO1 mRNA expression. The inhibition is both time- and concentration-dependent, requires inhibition of protein synthesis, and occurs at a transcriptional level. Inhibition of NQO1 transcription by CHX correlates with a rapid reduction of the CNC bZip (cap 'n' collar basic leucine zipper) transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) through the 26 S proteasome pathway. Moreover, blocking Nrf2 degradation with proteasome inhibitor MG132 increases the amount of Nrf2 and superinduces NQO1 in the presence of TCDD or tBHQ. Finally, genetic experiments using AhR (aryl hydrocarbon receptor)-, Arnt (aryl hydrocarbon receptor nuclear translocator)- or Nrf2-deficient cells reveal that, while induction of NQO1 by TCDD depends on the presence of AhR and Arnt, the basal and inducible expression of NQO1 by either TCDD or tBHQ requires functional Nrf2. The findings demonstrate a novel role of Nrf2 in the induction of NQO1 by TCDD and provide new insights into the mechanism by which Nrf2 regulates the induction of phase II enzymes by both phenolic antioxidants and AhR ligands.
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PMID:Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. 1451 Jun 36

CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] has been the subject of continued interest for over 30 years. As an anti-cancer agent, it represents one of the very few examples of a compound that shows real anti-tumor selectivity. Unfortunately, for the treatment of human disease, this anti-tumor selectivity was seen only in certain rat tumors. The basis for the anti-tumor selectivity of CB 1954 is that it is a prodrug that is enzymatically activated to generate a difunctional agent, which can form DNA-DNA interstrand crosslinks. The bioactivation of CB 1954 in rat cells involves the aerobic reduction of its 4-nitro group to a 4-hydroxylamine by the enzyme NQO1 (DT-diaphorase). The human form of NQO1 metabolizes CB 1954 much less efficiently than rat NQO1. Thus human tumors are insensitive to CB 1954. In view of the proven success of CB 1954 in the rat system, it would be highly desirable to re-create its anti-tumor activity in man. This has led to the development of CB 1954 analogs and other prodrugs activated by nitroreduction such, as those based on a self-immolative activation mechanism. A gene therapy-based approach for targeting cancer cells and making them sensitive to CB 1954 and related compounds has been developed. VDEPT (gene-directed enzyme prodrug therapy) has been used to express an E. coli nitroreductase in tumor cells and human tumor cells transduced to express this enzyme are very sensitive to prodrugs activated by nitroreduction. CB 1954 is in clinical trial for this application. Recently it has been shown that a latent nitroreductase is present in some human tumors. This is NQO2--an enzyme that requires for activity, the non-biogenic compound dihydronicotinamide riboside (NRH) as a cosubstrate. When active, NQO2 is 3000 times more effective than human DT-diaphorase in the reduction of CB 1954. NRH and reduced pyridinium derivatives that, like NRH, act as co-substrates for NQO2, produce a dramatic increase in the cytotoxicity of CB 1954 against human cell lines in vitro and its anti-tumor activity against certain human xenografts in vivo. NQO2 activity is substantially raised in tumor samples from colorectal and hepatoma patients (up to 14-fold). A phase I clinical trial of an NQO2 co-substrate with CB 1954 is scheduled.
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PMID:CB 1954: from the Walker tumor to NQO2 and VDEPT. 1452 7

Induction of cellular phase 2 detoxifying enzymes is associated with cancer preventive potential. Quinone reductase (QR) has been used as a prototype for anticarcinogenic phase 2 enzymes because of its widespread distribution in mammalian systems, large amplitude of inducer response, and ease of measurement in murine hepatoma cells. Methanol extract of Polyozellus multiplex, which shows a strong QR induction potential, was subjected to bioassay-guided fractionation, and polyozellin (PM1) appeared to be a major active component. In in vitro cultured cells (hepa1c1c7 and BPRc1 cells), polyozellin enhanced QR, glutathione S-transferase (GST) activities, and glutathione (GSH) content in a dose-dependent manner. The compound also significantly promoted differentiation of HL-60 human promyelocytic emia cells. In conclusion, polyozellin deserves further in vivo study to evaluate its potential as a cancer preventive agent.
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PMID:Polyozellin isolated from Polyozellus multiplex induces phase 2 enzymes in mouse hepatoma cells and differentiation in human myeloid leukaemic cell lines. 1475 31

The dioxin 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) induces phase I and II xenobiotic metabolizing enzymes (XME) which act sequentially to eliminate different classes of xenobiotics. The transcriptional effects of TCDD are generally mediated by the arylhydrocarbon receptor (AhR). We hypothesized that TCDD could also act indirectly, by increasing the activity of cytochrome P450 1A1 (CYP1A1), a phase I gene, which could then mediate the induction of other XME genes, such as the NAD(P)H:quinone oxidoreductase 1 (NQO1). To test this hypothesis, NQO1 gene expression was monitored after either overexpression of CYP1A1 or siRNA-mediated knock-down of CYP1A1 activity in the hepatoma cell line HepG2. Overexpression of CYP1A1 in the absence of TCDD was carried out using either adenoviral infection or the "Tet-off" system. Recombinant adenoviruses were produced encoding no protein, CYP1A1 (Ad1A1), or a mutated inactive CYP1A1 (Ad1A1mut). In the HepG2 Tet-off cell line, CYP1A1 expression was induced by the removal of doxycycline (dox) from the cell medium. Ad1A1 infection or dox removal induced CYP1A1 activity and H(2)O(2) production similarly to TCDD treatment. Moreover, in both systems, the amount of NQO1 mRNA increased to the same level as after TCDD treatment (approximately 2-fold). The UDP-glucuronosyl transferase 1A6 (UGT1A6) gene is also similarly regulated. NQO1 gene expression was not induced when mutant, inactive CYP1A1 was overexpressed or when the antioxidant N-acetyl cysteine (NAC) was added to Ad1A1. Finally, either NAC or siRNA directed against CYP1A1 mRNA decreased the induction of NQO1 gene expression by TCDD. We conclude that, after exposure to TCDD, the NQO1 gene expression can be controlled by CYP1A1 activity through an oxidative stress mediated pathway.
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PMID:Regulation of NAD(P)H:quinone oxidoreductase 1 gene expression by CYP1A1 activity. 1504 33


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