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)

Tiazofurin, an oncolytic drug, reduces PI kinase activity and arrests chiefly in S phase. Genistein, an inhibitor of PIP kinase, tyrosine kinase, and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both tiazofurin and genistein reduce second messenger IP3 concentration in ovarian carcinoma cells. Because genistein and tiazofurin attack different enzymic targets and arrest the cell cycle at different phases, we tested the hypothesis that tiazofurin might be synergistic with genistein. Human ovarian carcinoma OVCAR-5 cells were grown in flasks in monolayers. In growth inhibition assay for tiazofurin and genistein the IC50s were 26 and 18 microM, respectively, and in clonogenic assays the LC50s were 17 and 4 microM, respectively. Various combinations of the two drugs were tested. The best protocol took into consideration that tiazofurin decreased GTP concentration in cells by 50% at 12 h after administration. Tiazofurin (20 microM) and genistein (20 microM) as single agents reduced cell counts to 60% and 50%, respectively. The predicted value, as a sum of the effect of two drugs, would have been 30% of controls. However, genistein added 12 h after tiazofurin decreased cell counts to 8%, showing synergistic action of the two drugs for growth inhibition. Similar results were observed in the clonogenic assays, which also revealed synergistic cytotoxicity. The protocol yielding synergism might be of value in the clinical treatment of human ovarian carcinoma.
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PMID:Synergistic action of tiazofurin and genistein in human ovarian carcinoma cells. 970 Jul 22

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

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), an oncolytic drug, inhibits IMP DH (inosine 5'-monophosphate dehydrogenase, EC 1.1.1.205), reduces signal transduction activity and IP3 (inositol 1,4,5-trisphosphate) concentration and arrests the cell cycle chiefly in S phase. Genistein (4',5,7-trihydroxyisoflavone), an inhibitor of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase, EC 2.7.1.68), tyrosine kinase and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both drugs, as single agents, induce differentiation. Since tiazofurin and genistein attack different enzymic targets and arrest the cell cycle at different phases and they each induce differentiation, we tested the hypothesis that tiazofurin might be synergistic with genistein in inducing differentiation. Human leukemic K-562 cells were grown in suspension culture and were seeded in 24-well culture plates. In growth inhibition assays for tiazofurin and genistein IC50s (drug concentration that inhibits 50% of cell proliferation) were 7 and 37 microM, respectively. For tiazofurin and genistein the concentrations of drug that induce differentiation in 50% of the cells were 35 and 45 microM, respectively. Various combinations of these two drugs were tested. Since tiazofurin decreased GTP concentration in cells by 50% at 12 hr after administration, genistein (10 to 30 microM) was added 12 hr after tiazofurin (5 to 15 microM). Synergistic action on differentiation was obtained from all tiazofurin and genistein combinations and in most combinations on growth inhibition. The percent of differentiating cells induced by genistein (10 microM) and tiazofurin (10 microM) as single agents increased 1.1- and 2.8-fold, respectively, of the control values. The two drugs together caused 5.9-fold elevation in inducing differentiation. Similar action was observed on inhibition of proliferation.
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PMID:Synergistic action of tiazofurin and genistein on growth inhibition and differentiation of K-562 human leukemic cells. 983 41

The aim of this study was to identify the molecular mechanism of action of the isoflavone, genistein. Genistein at 0.15 mM caused MCF-7 apoptotic cell death, which was accompanied by cell cycle delay in the G2/M phase. Twenty-four hours post-treatment, 47.3% of the MCF-7 cells accumulated at G2/M, compared with 19.9% in the untreated controls. At 0.15 mM, genistein caused an increase in the steady-state levels of the wild-type tumour suppressor p53, which was attributed to stabilising the tumour suppressor protein, since p53 mRNA levels did not increase. Prior to the upregulation of p53, which became evident within 6 h of genistein treatment, there was increased bcl-2 phosphorylation at 30 min post-treatment. Although early changes (30-120 min) in the phosphotyrosine peptide patterns were not detected, after 24h, genistein inhibited phosphorylation of several peptides. These results suggest that genistein's dual roles of protein tyrosine kinase inhibitor and topoisomerase II inhibitor are essential for the initiation of apoptosis.
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PMID:Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells. 1002 17

Recent molecular-genetic studies have revealed that in the majority of patients with secondary leukemia induced by topoisomerase II (topo II) inhibitors and also with infantile acute leukemia (IAL), the breakpoints are clustered within scaffold attachment regions (SARs) of 3'-MLL-bcr near exon 9. Genistein, abundant in soybeans, is reported to be a potent nonintercalative topo II inhibitor. It interferes with the break-reseal reaction of topo II by stabilizing a cleavable complex, which in the presence of detergents, results in DNA strand breaks. The present study revealed that genistein induced chromatid-type aberrations, in which chromatid exchanges are often observed. Genistein seems to act in a manner very similar to that of VP-16, although the latter is reported to produce both chromatid- and chromosome-type aberrations. In view of this pharmacological similarity between genistein and VP-16, and also the similarity of breakpoint clustering regions within the MLL gene in reported cases with secondary leukemia and IAL, genistein may be largely responsible for the development of IAL.
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PMID:Infantile leukemia and soybeans--a hypothesis. 1072 Jan 57

The isoflavones, genistein and genistin, are cytotoxic in vitro (e.g. , inhibition of cell proliferation), due in part to inhibition of protein tyrosine kinase and DNA topoisomerase activities. Normal cell functions associated with these enzymatic activities could potentially be impaired in animals through ingestion of soybean products. In this study, cultured rat myogenic cells (L8) were used to determine whether genistein or genistin influences myoblast proliferation and fusion, and myotube protein synthesis and degradation. Genistein or genistin was dissolved in dimethylsulfoxide and included in the culture medium at 0, 1, 10 or 100 micromol/L. Myoblast proliferation was measured by methyl-3H-thymidine incorporation over 48 h. Myoblast differentiation was evaluated by the number of nuclei in multinucleated myotubes. Myotube protein synthesis was measured by 2-h 3H-amino acid incorporation into the myosin and total protein pools after acute (2 h) or chronic (24 h) exposure to similar treatments; protein degradation was measured by measuring radioactivity in protein pools following a time course of protein breakdown after myotube proteins were prelabeled with 3H-amino acids. Genistein or genistin strongly inhibited in vitro myoblast proliferation (P < 0.001) and fusion (P < 0.001) in a dose-dependent manner with effective genistein concentration as low as 1 micromol/L. Genistein or genistin inhibited protein accretion in myotubes (P < 0.001). Decreased protein accretion is largely a result of inhibition on cellular (myofibrillar) protein synthesis rate. No adverse effect on protein degradation was observed. Results suggest that if sufficient circulating concentrations are reached in tissues of animals consuming soy products, genistein/genistin can potentially affect normal muscle growth and development.
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PMID:Soybean isoflavones, genistein and genistin, inhibit rat myoblast proliferation, fusion and myotube protein synthesis. 1039 89

By using tissue miniunits, protein kinase modulators, and topoisomerase inhibitors in short-term incubation (0-90 min) we studied (1) the role of protein phosphorylation in the immediate control of DNA replication in the developing rat cerebral cortex and (2) the mechanism of action for genistein-mediated DNA synthesis inhibition. Genistein decreased the DNA synthesis within less than 30 min. None of the other protein kinase inhibitors examined (herbimycin A, staurosporine, calphostin-C) or the protein phosphatase inhibitor sodium orthovanadate inhibited DNA synthesis and they did not affect the genistein-mediated inhibition. The selective topoisomerase inhibitors camptothecin and etoposide decreased the DNA synthesis to an extent similar to that of genistein and within less than 30 min. In addition, the effects of these substances on topoisomerase I and II were studied. Etoposide and genistein but not herbimycin A, staurosporine, or calphostin-C strongly inhibited the activity of topoisomerase II. Our results (1) strongly suggest that the net rate of DNA replication during the S phase of the cell cycle is independent of protein phosphorylation and (2) indicate that the early inhibitory effect of genistein on DNA synthesis is mediated by topoisomerase II inhibition rather than protein tyrosine kinase inhibition.
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PMID:Early effects of protein kinase modulators on DNA synthesis in rat cerebral cortex. 1048 85

Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinase and DNA topoisomerase II activities. Genistein has been shown to have anticancer proliferation, differentiation and chemopreventive effects. In the present study, we have addressed the mechanism of action by which genistein suppressed the proliferation of p53-null human prostate carcinoma cells. Genistein significantly inhibited the cell growth, which effect was reversible, and induced dendrite-like structure. The inhibitory effects of genistein on cell growth proliferation were associated with a G2/M arrest in cell cycle progression concomitant with a marked inhibition of cyclin B1 and an induction of Cdk inhibitor p21 (WAF1/CIP1) in a p53-independent manner. Following genistein treatment of cells, an increased binding of p21 with Cdk2 and Cdc2 paralleled a significant decrease in Cdc2 and Cdk2 kinase activity with no change in Cdk2 and Cdc2 expression. Genistein also induced the activation of a p21 promoter reporter construct, utilizing a sequence distinct from the p53-binding site. Analysis of deletion constructs of the p21 promoter indicated that the response to genistein could be localized to the 300 base pairs proximal to the transcription start site. These data suggest that genistein may exert a strong anticarcinogenic effect, and that this effect possibly involves an induction of p21, which inhibits the threshold kinase activities of Cdks and associated cyclins, leading to a G2/M arrest in the cell cycle progression.
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PMID:p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells. 1076 3

Breast cancer is the most common cancer in women. Because genetics is believed to account for only 10-15% of breast cancer cases, the environment, including nutrition, is thought to play a significant role in predisposing women to this cancer. Studies of Asian women suggest that those who consume a traditional diet high in soy products have a low incidence of breast cancer, but that among emigrants to the United States, the second generation, but not the first, loses this protection. These findings suggest a possible common mechanism of action for breast cancer protection from early, specific nutritional exposure. Genistein, an isoflavone found in soy, has been reported to have weak estrogenic and antiestrogenic properties, to be an antioxidant, to inhibit topoisomerase II and angiogenesis, and to induce cell differentiation. In studies of the mammary glands of immature rats, we showed that genistein up-regulates the expression of the epidermal growth factor receptor shortly after treatment, which may be responsible for the increased cell proliferation seen at that age. We hypothesize that the early genistein action promotes cell differentiation that results in a less active epidermal growth factor signaling pathway in adulthood that, in turn, suppresses the development of mammary cancer. We speculate that breast cancer protection in Asian women consuming a traditional soy-containing diet is derived from early exposure to soybean products containing genistein. We believe that early events are essential for the benefits of cancer protection.
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PMID:Protection against breast cancer with genistein: a component of soy. 1083 23

Genistein--a soy derived isoflavone has recently attracted much attention of the medical scientific community. This compound was found to be a potent agent in both prophylaxis and treatment of cancer as well as other chronic diseases. The great interest that has focused on genistein led to the identification of numerous intracellular targets of its action in the live cell. At the molecular level, genistein inhibits the activity of ATP utilizing enzymes such as: tyrosine-specific protein kinases, topoisomerase II and enzymes involved in phosphatidylinositol turnover. Moreover, genistein can act via an estrogen receptor-mediated mechanism. At the level one step higher, i.e., at the cellular level, genistein induces apoptosis and differentiation in cancer cells, inhibits cell proliferation, modulates cell cycling, exerts antioxidant effects, inhibits angiogenesis, and suppresses osteoclast and lymphocyte functions. These activities make genistein a promising innovative agent in the treatment of cancer. Additionally, genistein health beneficial effects have been shown in osteoporosis, cardiovascular diseases and menopause. Genistein was also successfully used as an immunosuppressive agent both in vitro and in vivo. All these effects at the three biological levels of action need varied genistein concentrations and only some of them are relevant in people consuming soy-rich diet. The others would occur after purified genistein administration at higher doses. The main genistein advantage as a potential drug is its multidirectional action in the live cell and its very low toxicity.
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PMID:Biological properties of genistein. A review of in vitro and in vivo data. 1093 94


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