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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activities of protein tyrosine kinase and phosphatidylinositol turnover have been found to be associated with cell growth and differentiation. We examined the effects of some inhibitors for these biochemical activities in human myelogenous leukemia cells. Genistein, which is known to inhibit the activities of protein tyrosine kinase, phosphatidylinositol turnover and topoisomerase II, induced nitroblue tetrazolium (NBT) reduction and lysozyme activity in ML-1, HL-60 and U937 cells. Morphological studies showed that genistein-induced differentiation of myeloblastic ML-1 cells into promyelocytes and of promyelocytic HL-60 cells into mature granulocytes. The differentiation-inducing effect of genistein was augmented by addition of 1 alpha,25-dihydroxyvitamin D3 (VD3) or retinoic acid, VD3 being more effective than retinoic acid. Methyl 2,5-dihydroxycinamate, a protein tyrosine kinase inhibitor, had only a weak effect in inducing differentiation of ML-1 cells. On the other hand, psi-tectorigenin was more effective than genistein in inducing the differentiations of ML-1 and HL-60 cells. Psi-tectorigenin is reported to inhibit phosphatidylinositol turnover without inhibiting protein tyrosine kinase. Thus modulation of phosphatidylinositol turnover might be more important than that of protein tyrosine kinase activity for differentiation of some myelogenous leukemia cells.
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PMID:Effects of inhibitors of protein tyrosine kinase activity and/or phosphatidylinositol turnover on differentiation of some human myelomonocytic leukemia cells. 189 51

Genistein, an in vitro inhibitor of topoisomerase II and tyrosine kinases, elicited an inhibition of growth and increased melanin content in five human melanoma cell lines, after six days of treatment at a concentration of 45 microM. In two lines examined more thoroughly, HO and SK-MEL-131, treatment with genistein also increased other markers of differentiation, including tyrosinase activity, reactivity with CF21 monoclonal antibody, and dendrite-like structure formation. The genistein-evoked increases in melanin content and tyrosinase activity were concentration- and time-dependent. Treatment of HO and SK-MEL-131 cells with 45 microM genistein for 24 hr or 60-600 microM genistein for only 1 hr resulted in an increase in protein-linked DNA strand breaks. Our results suggest an association between the genistein-evoked, protein-linked, DNA strand breaks and the genistein-induced differentiation of human melanoma cells.
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PMID:Genistein-induced cell differentiation and protein-linked DNA strand breakage in human melanoma cells. 211 63

Genistein, an in vitro inhibitor of topoisomerase II and tyrosine kinases, suppressed growth and induced differentiation in HL-205 cells, a clonal population of the human promyelocytic HL-60 leukemia cells, and in K-562-J cells, a clonal population of the human erythroid K-562 leukemia cells. Maturing HL-205 cells acquired either granulocytic or monocytic markers, namely, reactivity with the murine OKM1 monoclonal antibody, expression of nitroblue tetrazolium dye reduction, and staining for nonspecific esterase. The maturing K-562-J cells stained with benzidine, which indicates the presence of hemoglobin, an erythroid maturation marker. Although the acquisition of the maturation markers in both HL-205 and K-562-J cells was time dependent up to 6 days, the kinetics of this induction differed between the two cell types. Despite the in vitro inhibitory effect of genistein, treatment of either HL-205 or K-562-J cells with 150 micrograms/ml genistein for up to 16 h did not alter topoisomerase II activity (as determined by the unknotting assay) in their nuclear extracts. Analysis with the anti-phosphotyrosine PY-20 murine monoclonal antibody indicated that treatment of K-562-J cells with genistein decreased the reactivity of the antibody with two of the cellular proteins. However, no reactivity with the PY-20 antibody was detected in untreated or genistein-treated HL-205 cells. An early event in the HL-205 and K-562-J cells, occurring after only 1 h of treatment with 30-200 micrograms/ml genistein, was the induction of DNA damage as measured by an alkaline elution assay. This damage may be a contributing factor in the genistein-induced cell differentiation in the HL-205 and K-562-J cells.
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PMID:Induction of differentiation and DNA strand breakage in human HL-60 and K-562 leukemia cells by genistein. 215 95

Genistein inhibited topoisomerase II and I; it increased the enzyme-DNA complex in L1210 cells at 1 micrograms/ml, and interfered with pBR322 DNA relaxation by the enzymes. To test the role of topoisomerase in the transformation by oncogenes, the effect of genistein on the transformation of NIH 3T3 cells by transfection with [Val 12]Ha-ras was compared with that of N-alpha-tosyl-L-lysyl-chloromethyl ketone (TLCK), since genistein inhibits tyrosine kinase as well as TLCK. Genistein reduced the number of foci of the transformed cells, and suppressed selectively the growth of ras-transformed NIH 3T3 cells but not normal NIH 3T3 cells. In contrast, TLCK did not affect the transformation. It inhibited the growth of the normal cells but not the transformed cells.
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PMID:Effect of genistein on topoisomerase activity and on the growth of [Val 12]Ha-ras-transformed NIH 3T3 cells. 284 17

The effects of genistein (one of the major soybean isoflavones), genistein (the glucosylated form of genistein) and etoposide (a topoisomerase 11 inhibitor) have been studied in mouse splenocytes in culture. Genistein (25 microM), genistein (25 microM) and etoposide (0.1 microM) all induced the production of large numbers of micronuclei; however, genistein at 12.5 or 2.5 microM had no clastogenic effect. In a second study, mice were gavaged with 20 mg genistein/kg body weight/day for 5 days (approximately equivalent to a 70 kg human consuming 2.8 kg soybeans/day) and the micronucleus frequency was determined. There was no observable increase in the micronucleus frequency even though the plasma genistein levels in the treated animals were found to be 9.2 +/- 2.0 microM compared with 0.1 +/- 0.0004 microM in the control animals. The results show that even though genistein is capable of inducing micronucleus formation, an event associated with genetic damage, plasma levels are unlikely to be sufficiently elevated to produce such an effect.
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PMID:Induction of micronucleus formation in mouse splenocytes by the soy isoflavone genistein in vitro but not in vivo. 759 May 38

Genistein, an isoflavonoid derivative initially described as an in vitro protein tyrosine kinase inhibitor, also inhibits mammalian DNA topoisomerase II both in vitro and in vivo. From a human leukaemic T cell line (CCRF-CEM), two genistein-resistant cell lines, which grow in the presence of 50 and 150 microM genistein, respectively, were selected and designated CEM/GN50 and CEM/GN150. Flow cytometry and karyotype analyses revealed that more than 95% of the parental cells were tetraploid whereas both resistant sublines were essentially diploid and were likely derived from the diploid fraction in the initial population. The CEM/GN cells were 3- to 4-fold resistant to genistein, and highly cross-resistant to certain metabolic inhibitors such as cytosine-arabinoside (50-fold) and 5-fluoro-2'-deoxyuridine (5000-fold). This resistance was associated with a markedly decreased uptake of thymidine and a 10-fold reduction in thymidine kinase activity. The CEM/GM cells were also 15- to 30-fold cross-resistant to topoisomerase inhibitors (etoposide, m-AMSA, 2-Me-9-OH-ellipticinium). Comparison of topoisomerase II activities in the sensitive and resistant cells showed: (i) an approximately 2-fold reduced decatenation activity in nuclear extracts from the resistant cells; (ii) an approximate 30% reduction in DNA-protein cross-links in etoposide-treated resistant cells; and (iii) a markedly reduced expression of the topoisomerase II beta isoform. These data, consistent with our previous results, indicate that the cytotoxicity of genistein is at least in part related to its capacity to inhibit DNA topoisomerase II.
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PMID:Genistein resistance in human leukaemic CCRF-CEM cells: selection of a diploid cell line with reduced DNA topoisomerase II beta isoform. 763 61

We tested the potential impact of tyrosine phosphorylation on the expression of the c-myc gene in two colon cancer cell lines, HCT8 and SW837. We found that the protein tyrosine kinase inhibitor genistein causes a decrease in the abundance of c-myc RNA and an inhibition of proliferation with a similar dose response. Geldanamycin, a mechanistically different tyrosine kinase inhibitor, also causes a decrease in both the expression of c-myc RNA and proliferation. Genistein has also been found to inhibit topoisomerase II, but the topoisomerase II inhibitor novobiocin did not lower the expression of c-myc. The most likely interpretation is that inhibition of protein tyrosine kinase activity caused a decrease in c-myc expression in these cells. The impact of tyrosine phosphorylation on the expression of the c-myc gene is further supported by the finding that inhibition of phosphotyrosine phosphatase using orthovanadate causes an increase in the level of c-myc RNA. The effect of genistein on HCT8 cells is not dependent on the synthesis of new protein and does not involve an alteration in the stability of the message. Analysis of transcription in the c-myc gene reveals a more complicated picture with a decrease in initiation and an increase in elongation but no net change in transcription. We speculate that the genistein induced reduction in myc expression is the result of a posttranscriptional intranuclear event(s).
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PMID:Influence of protein tyrosine phosphorylation on the expression of the c-myc oncogene in cancer of the large bowel. 764 26

Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II without inhibiting topo I. Flavonoids demonstrating potent topo I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3', and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid topo I inhibitory action. A C-2, C-3 double bond was also required, but when the A ring is opened, the requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage complex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavage complex, but prunetin, quercetin, kaempferol, and apigenin stabilized the topo II DNA-complex. Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme. These results are of use for the selection of flavonoids that can inhibit specific topoisomerases at specific stages of the topoisomerization reaction.
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PMID:Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. 776 90

Although data from epidemiological studies and cancer models suggest that genistein plays an important role in cancer prevention, the biochemical target(s) of genistein action is (are) not known. Genistein is a potent in vitro inhibitor of protein tyrosine kinase (PTK) activity, especially that of the epidermal growth factor receptor (EGF-R), having little effect on serine/threonine kinases. This led to the suggestion that genistein might exert its anti-cancer effects through inhibiting the activity of EGF-R PTK, or other crucial PTK's in vivo. Subsequent studies on intact tumor cell lines demonstrated that EGF-R and other growth factor receptors are able to transmit mitogenic signals in the presence of genistein. In fact, it is difficult to detect decreases in the tyrosine phosphorylation of discrete proteins after genistein treatment. Other mechanisms for the effect of genistein have been suggested from in vitro and cell culture data. Genistein not only inhibits the activity of purified topoisomerase II in vitro, but also leads to the accumulation of protein-associated single strand breaks in whole cells. Genistein also inhibits the production of reactive oxygen species which may lead to tissue damage and DNA modification. Additionally, genistein acts as a weak estrogen, modifies cellular differentiation programs, inhibits angiogenesis. modulates cell cycle events and may precipitate apoptosis. However, few of the above mechanisms in tumor cells are sensitive to the physiological serum concentrations of genistein (< 18.5 mumol/L, or < 5 micrograms/mL). Primary, nontransformed human mammary epithelial cells, which have a much greater sensitivity to genistein, would be a better system for the study of these mechanisms.
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PMID:Evaluation of the biochemical targets of genistein in tumor cells. 788 65

Genistein is an inhibitor of the enzymes protein tyrosine kinase and topoisomerase-II. It induces G2-phase arrest in human Jurkat and murine P388 leukemia cells at concentrations at which it is also cytotoxic. The effects of genistein have been investigated on Jurkat and P388 leukemia sublines that manifest multidrug resistance. Cells that possess altered topoisomerase-II activity ("atypical" multidrug resistance) are resistant to both the G2 phase-arresting and cytotoxic effects of genistein. The ability of genistein to impede progression through the cell cycle and kill cells is similar to that of amsacrine, a classical topoisomerase-II poison. This result identifies topoisomerase-II rather than tyrosine kinase activity as the target of genistein-mediated cytotoxicity and G2-phase arrest.
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PMID:Comparison of the effects of genistein and amsacrine on leukemia cell proliferation. 791 50


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