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)

Some marine animals are rich sources of unique polycyclic aromatic alkaloids that are cytotoxic against tumor cell lines and effective in mouse tumor xenograft models. Ascididemin is a pyridoacridine alkaloid originally derived from a Didemnum sp. tunicate. It has potent cytotoxicity against tumor cells in vitro and in vivo. Preclinical screening at NCI revealed the antineoplastic activities of ascididemin and a synthetic analogue 48. Ascididemin has been reported to inhibit topoisomerase II and induce topoisomerase II-mediated DNA cleavage. This study, however, focuses on the unique ability of ascididemin and two synthetic analogues (48 and 109) to cleave DNA in the absence of topoisomerase I or II. An in vitro assay revealed their concentration-dependent ability to cleave DNA and identified dithiothreitol as the sole requirement for maximal activity. On the basis of shared structural features of the three analogues, a double N-bay region and iminoquinone heterocyclic ring, two possible mechanisms of action were hypothesized: (1) generation of reactive oxygen species facilitated by metal binding to the common phenanthroline bay region, and (2) production of reactive oxygen species by direct reduction of the iminoquinone moiety. Experimental results supported direct iminoquinone reduction and ROS generation as the mechanism of ascididemin cytotoxicity. Antioxidants protected against DNA cleavage in vitro and protected cultured Chinese hamster ovary cells from toxicity. Additionally, it was shown that cells deficient in the ability to repair reactive oxygen species damage to their DNA were more susceptible to ascididemin and analogues than repair competent cells. Ascididemin-treated cells were also shown to induce oxygen-stress related proteins, further implicating the production of reactive oxygen species as the mechanism of cytotoxicity for these molecules.
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PMID:Mechanism of ascididemin-induced cytotoxicity. 1258 81

Fenton systems (H2O2/Fe(II) or H2O2/Cu(II)) inhibited Trypanosoma cruzi and Crithidia fasciculata topoisomerase I activity. About 61-71% inactivation was produced by 25 mM Fe(II) or Cu(II) with 3 mM H2O2. Thiol compounds and free radicals scavengers prevented the Fenton systems effects, depending on the topoisomerase assayed. With the T. cruzi enzyme, reduced glutathione, DL-dithiothreitol, cysteine and N-acetyl-L-cysteine entirely prevented the effect of the H2O2/Fe(II) system, mannitol protected 37%, whereas histidine and ethanol were ineffective. With C. fasciculata topoisomerase, reduced glutathione, DL-dithiothreitol and N-acetyl-L-cysteine protected 100%, cysteine, histidine and mannitol protected 28, 34 and 48% respectively, whereas ethanol was ineffective. With the H2O2/Cu(II) system and T. cruzi topoisomerase, DL-dithiothreitol and histidine protected 100% and 60%, respectively but the other assayed protectors were less effective. Similar results were obtained with the C. fasciculata enzyme. Topoisomerase inactivation by H2O2/Fe(II) or H2O2/Cu(II) systems was irreversible since they were not reverted by the more effective enzyme protectors. It is suggested that topoisomerases could act either as scavengers of "reactive oxygen species" (ROS) generated by Fenton systems or bind the corresponding metal ions, whose redox cycling would generate reactive oxygen species "in situ".
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PMID:[Inhibitory action of Fenton systems on topoisomerase I from Trypanosoma cruzi and Crithidia fasciculata]]. 1292 Sep 88

Based on co-crystal structures of human topoisomerase I with bound DNA, Lys(532) makes a minor groove contact with the strongly preferred thymidine residue at the site of covalent attachment (-1 position). Replacement of Lys(532) with either arginine or alanine has essentially no effect on the sequence preference of the enzyme, indicating that this interaction is not required for the preference for a T at the -1 position. Although both the cleavage and religation activities of the K532R mutant enzyme are reduced, cleavage is reduced to a greater extent than religation. The reverse is true for the K532A mutant enzyme with religation so impaired that the nicked intermediate accumulates during plasmid relaxation assays. Consistent with the shift in the cleavage religation equilibrium toward cleavage for the K532A mutant enzyme, expression of the mutant enzyme in Saccharomyces cerevisiae is cytotoxic, and thus this mutant enzyme mimics the effects of the anticancer drug camptothecin. Cleavage assays with the mutant enzymes using an oligonucleotide containing a 5'-bridging phosphorothiolate indicate that Lys(532) functions as a general acid during cleavage to protonate the leaving 5'-oxygen. It is possible that the contact with the -1 base is important during catalysis to provide positional rigidity to the active site. The corresponding residues in the vaccinia virus topoisomerase and the tyrosine recombinases may have similar critical roles in catalysis.
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PMID:The role of lysine 532 in the catalytic mechanism of human topoisomerase I. 1459 10

Cultured rat embryonic cortical neurons undergo apoptosis when treated with the topoisomerase-I inhibitor camptothecin. Pharmacological or molecular caspase inhibition prevents apoptosis, but the neurons still die in a delayed nonapoptotic manner. Here we examine the mechanisms leading to such caspase-independent death, focusing on events related to mitochondrial malfunction, which accompanies this delayed death. Given that mitochondria are the major source of ATP in primary neurons, we examined the cellular energy state. Mitochondrially generated ATP was specifically reduced in neurons treated with camptothecin and Boc-aspartyl-fluoromethylketone. Augmentation of cellular ATP by manipulation of the glucose content in the cultures led to an increase in survival specifically in delayed caspase-independent but not early caspase-dependent death. As another possible consequence of mitochondrial malfunction, we found an induction of reactive oxygen species in delayed death. The free radical scavenger Tempol, but not other classes of antioxidants, reduced oxidative stress and promoted survival. Other potential events known to be a direct or indirect consequence of mitochondrial dysfunction, such as the induction of autophagy, release of apoptosis-inducing factor, or opening of the mitochondrial permeability transition pore, were not found to play a significant role in caspase-independent neuronal death. Combining the strategies of increasing intracellular ATP and reducing free radicals led to an additive increase in neuronal survival. We conclude that energy failure and free radical generation contribute to caspase-independent neuronal death. Both could represent potential targets for therapeutic interventions complementary to caspase inhibition.
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PMID:Mechanisms of caspase-independent neuronal death: energy depletion and free radical generation. 1465 58

Fenton systems (H(2)O(2)/Fe(II) or H(2)O(2)/Cu(II)) inhibited Trypanosoma cruzi and Crithidia fasciculata topoisomerase I activity. About 61-71% inactivation was produced by 25 microM Fe(II) or Cu(II) with 3.0 mM H(2)O(2). Thiol compounds and free radical scavengers prevented Fenton system effects, depending on the topoisomerase assayed. With the T. cruzi enzyme, reduced glutathione (GSH), dithiothreitol (DTT), cysteine and N-acetyl-L-cysteine (NAC) entirely prevented the effect of the H(2)O(2)/Fe(II) system; mannitol protected 37%, whereas histidine and ethanol were ineffective. With C. fasciculata topoisomerase, GSH, DTT and NAC protected 100%, cysteine, histidine and mannitol protected 28%, 34% and 48%, respectively, whereas ethanol was ineffective. With the H(2)O(2)/Cu(II) system and T. cruzi topoisomerase, DTT and histidine protected 100% and 60%, respectively, but the other assayed protectors were less effective. Similar results were obtained with the C. fasciculata enzyme. Topoisomerase inactivation by the H(2)O(2)/Fe(II) or H(2)O(2)/Cu(II) systems proved to be irreversible since it was not reversed by the more effective enzyme protectors. It is suggested that topoisomerases could act either as targets of 'reactive oxygen species' (ROS) generated by Fenton systems or bind the corresponding metal ions, whose redox cycling would generate reactive oxygen species in situ.
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PMID:Inactivation of Trypanosoma cruzi and Crithidia fasciculata topoisomerase I by Fenton systems. 1498 68

Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1alpha to a hypoxia-responsive element (positions -8484 to -8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.
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PMID:Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. 1502 76

Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by L-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis.
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PMID:Glutathione depletion induced by c-Myc downregulation triggers apoptosis on treatment with alkylating agents. 1515 31

There is growing recognition that carcinogenic risk extrapolation to low doses (and standard setting) should consider the mode of action of a given chemical. So far, there is agreement on distinguishing between genotoxic and nongenotoxic chemicals; yet, further differentiations seem appropriate. For genotoxic carcinogens, case studies of chemicals point to many possibilities for assessing carcinogenic risk. There are numerous, apparently genotoxic carcinogens where practical thresholds are a matter of discussion. For instance, positive data of chromosomal effects only, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses. There is a wide consensus that for non-DNA-reactive genotoxicants, such as aneugens, thresholds should be defined. Specific mechanisms of clastogenicity have been repeatedly addressed as also having thresholds, such as topoisomerase II poisons, or mechanisms based on reactive oxygen. These and other arguments together lead to the distinction of four groups of carcinogens, which have been introduced (C. Streffer et al., 2004, Springer-Verlag). There are nonthreshold genotoxic carcinogens (for low-dose risk assessment, the linear nonthreshold [LNT] model appears appropriate); genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported (in these cases the LNT model is used as a default assumption, based on the scientific uncertainty and backed by the precautionary principle); genotoxic carcinogens for which a practical threshold is supported; and nongenotoxic carcinogens and non-DNA-reactive carcinogens (for these compounds a true [perfect] threshold is associated with a clearly founded no-observed-adverse-effect level).
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PMID:Human carcinogenic risk evaluation, part II: contributions of the EUROTOX specialty section for carcinogenesis. 1515 28

Existing systems of classification of carcinogens are a matter of discussion, world-wide. There is agreement that it should be distinguished between genotoxic and non-genotoxic chemicals. The risk assessment approach used for non-genotoxic chemicals is similar among different regulatory bodies: insertion of an uncertainty (safety) factor permits the derivation of permissible exposure levels at which no relevant human cancer risks are anticipated. For genotoxic carcinogens, case studies of chemicals point to a whole array of possibilities. Positive data of chromosomal effects only, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses. Non-DNA-reactive genotoxins, such as topoisomerase inhibitors or inhibitors of the spindle apparatus are considered in this respect. In such cases, arguments are in favour of the existence of "practical" thresholds. Taking existing concepts together, it is proposed to basically distinguish between "perfect" and "practical" thresholds. There is a wide consensus that for non-DNA-reactive genotoxins such as aneugens (aneuploidy, chromosome loss, non-disjunction) thresholds should be defined. It is being discussed as to whether the identification of possible threshold effects should also include other mechanisms of genotoxicity, in addition to aneugenic effects. Specific mechanisms of clastogenicity have been repeatedly addressed as also having thresholds, such as topoisomerase II poisons or mechanisms based on reactive oxygen. Oxidative stress as an important mechanism is triggered by exposure to exogenous factors such as ultraviolet (UV) and ionizing radiation, anoxia and hyperoxia, and by chemicals producing reactive oxygen species. The idea is receiving increased support that reactive oxygen species (ROS)-mediated processes of carcinogenesis have practical thresholds. Since reactive oxygen species are genotoxic in principle, questions arise whether chemicals that increase ROS production will superimpose to an endogenously produced background level of DNA lesions, related to mechanisms that may result in non-linear dose-effect relationships. The existence of "endogenous" DNA adducts has been generally accepted, and possible regulatory implications of the presence of endogenous carcinogens have been discussed. It is now becoming evident that a diversity of methods of carcinogenic risk extrapolation to low doses must be considered, dependent on the mode of action. Although there is an increasing international awareness of these developments, the system of classification of carcinogens of the European Union still remains static. This should be changed, as the philosophy of separation of a strictly sequential "hazard assessment" and "risk assessment" appears out-of-date.
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PMID:Carcinogenicity categorization of chemicals-new aspects to be considered in a European perspective. 1517 38

Marine organisms and especially those living in tidal zones are confronted with dramatic changes in their environment such as temperature fluctuations on a daily and/or seasonal basis. In the present study, we investigated whether these parameters affect expression of multixenobiotic resistance (MXR)-related genes that serve as a first line of defense against a broad spectrum of natural and man-made toxicants. Expression of MXR-related genes seems to be an appropriate biomarker to determine hazardous effects of chemicals in contaminated marine habitats. The interference of natural environmental factors in the expression of biomarkers is an important issue with respect to the use of biomarkers in monitoring biological effects of pollutants, making interpretations difficult. We studied the effects of temperature, salinity and oxygen supply (anaerobiosis) on expression of MXR-related genes in gills and digestive gland of the blue mussel Mytilus edulis in order to differentiate between pollution-induced stress and responses to natural environmental variations. We found changes in expression levels of P-glycoprotein (pgp), major vault protein (mvp), topoisomerase II (topoII), heat shock protein 70 (hsp70), but not of the multidrug resistance-related protein (mrp2) genes, in laboratory experiments in relation to high temperature, low salinity and anaerobiosis but not low temperature. These effects of environmental factors have to be considered in sampling strategies for monitoring programmes to prevent false interpretation of results.
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PMID:Regulation of expression of multixenobiotic resistance (MXR) genes by environmental factors in the blue mussel Mytilus edulis. 1521 Feb 93


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