Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of topoisomerase inhibitors on human immunodeficiency virus type 1 (HIV-1) infection of H9 cells in cell culture. Infection is blocked or substantially reduced by the topoisomerase I inhibitor camptothecin (CPT), but not by two topoisomerase II inhibitors. Significant reduction (greater than or equal to 90%) in the amount of virus released, as measured by reverse transcriptase, is obtained if the cells are treated for 1 h with 0.01-0.02 microM CPT at the time of virus infection, and expression of viral proteins is also blocked. CPT is also shown to reduce the level of infection when chronically infected cells are cocultivated with uninfected cells. These results with CPT suggest that this compound may represent a new class of drugs with antiretroviral potential.
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PMID:Inhibition of human immunodeficiency virus (HIV-1) replication in vitro by noncytotoxic doses of camptothecin, a topoisomerase I inhibitor. 170 42

Two naturally occurring lignanolides, isolated from the tropical climbing shrub Ipomoea cairica, (-)-arctigenin and (-)-trachelogenin, were found to inhibit strongly replication of human immunodeficiency virus type 1 (HIV-1; strain HTLV-III B) in vitro. At a concentration of 0.5 microM, (-)-arctigenin and (-)-trachelogenin inhibited the expression of HIV-1 proteins p17 and p24 by 80-90% and 60-70%, respectively. The reverse transcriptase activity in the culture fluids was reduced by 80-90% when the cells (HTLV-III B/H9) were cultivated in the presence of 0.5 microM (-)-arctigenin or 1 microM (-)-trachelogenin. At the same concentrations, the formation of syncytia in the HTLV-III B/H9-Jurkat cell system was inhibited by the compounds by more than 80%. A series of other lignan type compounds displayed no anti-HIV activity. Studying the molecular mechanism of action of (-)-arctigenin and (-)-trachelogenin we found that both compounds are efficient inhibitors of the nuclear matrix-associated DNA topoisomerase II activity, particularly of the enzyme from HIV-1-infected cells. Our results suggest that both compounds prevent the increase of topoisomerase II activity, involved in virus replication, after infection of cells with HIV-1.
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PMID:Differential in vitro anti-HIV activity of natural lignans. 196 81

In a previous paper, we determined that treatment of lymphocytes with nonviable preparations of human immunodeficiency virus type 1 (HIV-1) results in an impairment of the phosphatidylinositol/protein kinase C pathway, most likely due to an inhibition of the cleavage of phosphatidylinositol bisphosphate into inositol trisphosphate and diacylglycerol, mediated by phospholipase C. Here we show that one consequence of these changes is a reduced phosphorylation of nuclear matrix-associated DNA topoisomerase II, resulting in an inhibition of the activity of this enzyme. Antibodies to the viral proteins suppressed the inhibitory effects caused by the HIV-1 preparation. Furthermore, the phytohemagglutinin A-caused augmentation of nuclear matrix-associated DNA polymerase alpha and beta activities was found to be abolished by coincubation with the HIV preparation or with the HIV-1 gp120. The phytohemagglutinin A-enhanced matrix association and processivity of DNA polymerase alpha was determined to be reduced if the lymphocytes were in contact with HIV-1 preparation. These results suggest that the reduced proliferative response of lymphocytes to phytohemagglutinin A in the presence of disrupted HIV-1 preparation is due to inhibition of at least two, perhaps separate, pathways, one involving protein kinase C resulting in a reduced phosphorylation of DNA topoisomerase II and the other changing the state of matrix association of DNA polymerase alpha and beta.
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PMID:Effect of nonviable preparations from human immunodeficiency virus type 1 on nuclear matrix-associated DNA polymerase alpha and DNA topoisomerase II activities. 215 2

Infection of H9 cells with human immunodeficiency virus type 1 (HIV-1) was found to decrease the phosphorylation of DNA topoisomerase II during the initial phase of infection. Simultaneously, with a later overshoot of phosphorylation and the subsequent activation of DNA topoisomerase II, the production of HIV-1 started. Applying three new protein kinase C inhibitors from the class of O-alkylglycerophospholipids we demonstrated that inhibition of protein kinase C-mediated phosphorylation of DNA topoisomerase II resulted in an inhibition of HIV-1 production. Based on the differential effect of the two protein kinase C activators, phorbol ester and bryostatin, we conclude that phosphorylation of DNA topoisomerase II is mediated by the form alpha and gamma of protein kinase C. These data suggest that agents which inhibit these two forms of protein kinase C are also potential candidates for an anti-HIV therapy.
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PMID:Alteration of DNA topoisomerase II activity during infection of H9 cells by human immunodeficiency virus type 1 in vitro: a target for potential therapeutic agents. 217 25

Retroviral growth requires as an obligatory step the integration of a DNA copy of the viral RNA into the genomic DNA of the host. Recombinant human immunodeficiency virus type I (HIV-1) integrase (IN) expressed in Escherichia coli efficiently catalyzes the overall in vitro integration reaction, namely, the processing of the LTR ends and the strand transfer reaction. Using the 3' end of synthetic oligonucleotides which match the termini of the HIV-I U5 LTR as substrate and supercoiled pSP65 DNA as target, we have measured the effect of various topoisomerase inhibitors on the functional activity of the IN protein. Among the various drugs tested, the antitumor drug 2N-Methyl, 9-hydroxyellipticinium (NMHE) displays a marked inhibitory effect on the IN-catalyzed U5 insertion. This effect is related to the DNA binding properties of the drug rather than to a selective effect on the IN protein or the DNA-IN protein complex.
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PMID:Effect of topoisomerase inhibitors on the in vitro HIV DNA integration reaction. 838 50

In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of chemicals, including topoisomerase inhibitors, antimalarial agents, DNA binders, naphthoquinones, the flavone quercetin, and caffeic acid phenethyl ester as potential human immunodeficiency virus type 1 integrase inhibitors. Our results show that although several topoisomerase inhibitors--including doxorubicin, mitoxantrone, ellipticines, and quercetin--are potent integrase inhibitors, other topoisomerase inhibitors--such as amsacrine, etoposide, teniposide, and camptothecin--are inactive. Other intercalators, such as chloroquine and the bifunctional intercalator ditercalinium, are also active. However, DNA binding does not correlate closely with integrase inhibition. The intercalator 9-aminoacridine and the polyamine DNA minor-groove binders spermine, spermidine, and distamycin have no effect, whereas the non-DNA binders primaquine, 5,8-dihydroxy-1,4-naphthoquinone, and caffeic acid phenethyl ester inhibit the integrase. Caffeic acid phenethyl ester was the only compound that inhibited the integration step to a substantially greater degree than the initial cleavage step of the enzyme. A model of 5,8-dihydroxy-1,4-naphthoquinone interaction with the zinc finger region of the retroviral integrase protein is proposed.
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PMID:Inhibitors of human immunodeficiency virus integrase. 846 Jan 51

Ataxia telangiectasia (AT) patients show variable degrees of immunodeficiency and a higher than normal predisposition to lymphoid malignancies. AT cells are characterized by spontaneous chromosome instability resulting in chromosome breakage and in non random chromosome rearrangements. Sequential cytogenetic studies on T-lymphocytes from an AT patient showed the progressive development of a clone bearing a tandem translocation t(14;14)(q11;q32). The abnormal clone had spontaneous chromosome rearrangements. Compared to non clonal cells, the abnormal clone displayed a higher frequency of spontaneous chromosome rearrangements. In only the clonal cells we observed two particular and predominant rearrangements: isodicentric chromosomes and telomeric associations which may derive from faulty recombination. Chromosome instability induced by the etoposide VP16, a DNA topoisomerase II inhibitor, was evaluated in terms of chromosome breakage and SCE frequency. T-lymphocytes from the AT patient showed hypersensitivity to VP16 significantly higher than normal T-lymphocytes. The chromosome instability induced by VP16 is significantly higher in clonal than in non clonal cells, whilst the chromosome instability induced by the radiomimetic drug bleomycin is not significantly different in the two AT lymphocyte subpopulations. The different spontaneous chromosome instability in clonal and non clonal cells together with their different behavior after treatment with only VP16, suggest that clonal cells bearing the tandem translocation could have increased faulty recombination. Given the presence of translocations t(14;14)(q11;q32) in T-prolymphocytic leukemias and T-cell tumors of non AT patients, our findings suggest that VP16 could be considered an antineoplastic treatment particularly indicated in these patients.
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PMID:VP16 hypersensitivity and increased faulty recombination in ataxia telangiectasia lymphocytes characterized by the tandem translocation t(14;14)(q11;q32). 862 39

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5 revealed a 1.1-kb intronic fragment followed by a related ORF of 2.5 kb that encodes the near full-length ORF for hTOP3, the first mammalian topoisomerase III to be identified. Endogenous expression of hTOP3 was found in all human tissues tested. Both pCAT4.5 and an antisense hTOP3 construct were able to inhibit spontaneous and radiation-induced apoptosis in A-T fibroblasts, whereas overexpression of a full-length hTOP3 cDNA did not. We postulate that topoisomerase III may be deregulated in A-T cells and that CAT4.5 complements the A-T phenotype via a dominant-negative mechanism. Furthermore, functional correction of hyper-recombination in A-T cells by CAT4.5 supports the hypothesis that the hTOP3 topoisomerase is involved in the control of genomic stability, perhaps in concert with the Bloom or Werner syndrome DNA helicases.
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PMID:Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype. 911 25

Topotecan (TPT), a known inhibitor of topoisomerase I, has previously been shown to inhibit the replication of several viruses. The mechanism of inhibition was proposed to be the inhibition of topoisomerase I. We report that TPT decreased replication of human immunodeficiency virus type 1 (HIV-1) in CPT-K5, a cell line with a topoisomerase I mutation. TPT inhibited production of HIV-1 RNA and p24 in CPT-K5 and wild-type cells equally effectively. The antiviral effects of TPT were observed not only in the topoisomerase-mutated CPT-K5 line but also in peripheral blood mononuclear cells (PBMC) acutely infected with clinical isolates and in OM10.1 cells latently infected with HIV and activated by tumor necrosis factor alpha. Little toxicity from TPT was noted in HIV-1-infected PBMC and in CPT-K5 and OM10.1 cells as measured by cell growth and proliferation assays. These observations suggest that TPT targets factors in virus replication other than cellular topoisomerase I and inhibits cytokine-mediated activation in latently infected cells by means other than cytotoxicity. These results suggest a potential for TPT and for other camptothecins in anti-HIV therapy alone and in combination with other antiretroviral drugs.
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PMID:Topotecan inhibits human immunodeficiency virus type 1 infection through a topoisomerase-independent mechanism in a cell line with altered topoisomerase I. 914 55

Protein tyrosine kinase (PTK) phosphorylation is involved in cellular proliferation and differentiation processes that are key factors for human immunodeficiency virus type 1 (HIV-1) regulation in infected monocytic cells. Short-term exposure of the chronically infected promyelocytic OM10 cell line with the PTK inhibitor genistein induced a dose-dependent increase in p24 antigen production in culture supernatants. This induction persisted in the presence of the reverse transcriptase inhibitor, zidovudine, and was associated with an increased transcription of HIV-1 multiply spliced and unspliced RNAs, suggesting a transcriptional mechanism targeting the integrated provirus. Genistein induced cell differentiation, apoptosis, and a G2 arrest in the OM10 cells. Cell differentiation and apoptosis were not directly involved in the observed increase in HIV-1 replication that was closely linked to genistein-induced G2 arrest. Alleviation of the G2 arrest by pentoxyfylline resulted in a concomitant reduction of HIV-1 to baseline replication. Additionally, by flow cytometry, a significant increase in the number of p24 antigen-expressing cells was observed in cells arrested in G2 compared to those located in G1 or S. Tyrosine kinase inhibition was found not to be essential for enhanced viral replication, which seemed to be related to two other properties of genistein, inhibition of topoisomerase II activity and inhibition of phosphotidylinositol turnover. These findings are consistent with the recent observation that HIV-1 Vpr induces viral replication through preventing proliferation of cells by arresting them in G2 of the cell cycle and strongly suggest that manipulation of the cell cycle plays an important role in HIV-1 pathogenesis.
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PMID:Human immunodeficiency virus type 1 induction mediated by genistein is linked to cell cycle arrest in G2. 973 59


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