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)

In previous studies we have reported that preactivated merocyanine 540 (pMC540) and its chemically synthesized isolates merocil and merodantoin mediate their preferential cytotoxicity towards certain types of malignant cells including human breast cancer cells in vitro and in vivo. The mechanism of cytotoxic action appears to be, in part, via initial interaction with topoisomerase II leading to apoptosis. To further build upon these findings we now show that pMC540 and merodantoin disrupt mitochondrial morphology and function in intact MCF-7 human breast cancer cells as seen by their causing the release of rhodamine 123 from prestained cells, a rapid reduction in ATP levels, inhibition of succinate dehydrogenase activity and oxygen consumption. These data suggest that mitochondria may also be an important target for the cytotoxic action of pMC540 and merodantoin mediated through disruption of the energy balance.
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PMID:Relationship of mitochondrial function and cellular adenosine triphosphate levels to pMC540 and merodantoin cytotoxicity in MCF-7 human breast cancer cells. 757 58

Internucleosomal DNA fragmentation and cell death induced by dexamethasone in rat thymocytes were inhibited when cells were cultured in 95% N2/5% CO2 atmosphere, in which oxygen was rapidly reduced to under 0.5%. DNA fragmentation was delayed by a less severe hypoxia in 5% oxygen whilst in cell cultured in high oxygen atmosphere (95% O2) cell death was increased. On the other hand, prolonged oxygen deprivation caused an increase of spontaneous apoptotic cell death. Hypoxia also inhibited DNA fragmentation induced by calcium ionophore A23187, but not by topoisomerase inhibitor camptothecin. These data support the hypothesis of the involvement of oxygen reactive species in calcium-mediated apoptosis and suggest a complex role of oxygen in the modulation of programmed cell death.
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PMID:Oxygen tension influences DNA fragmentation and cell death in glucocorticoid-treated thymocytes. 762 42

The pH dependences of the internal equilibrium (Kcl) and rate constants for site-specific DNA strand cleavage (kcl) and resealing (kr) catalyzed by Vaccinia DNA topoisomerase I have been investigated using single-turnover conditions in the pH range 4.6-9.8 at 20 degrees C. The pH dependence of the rate constant for strand cleavage (kcl) shows a bell-shaped profile with apparent pKa values of 6.3 +/- 0.2 and 8.4 +/- 0.2, suggesting base catalysis of the attack of the active site Tyr-274 on the phosphodiester phosphorus, and acid catalysis of the expulsion of the 5'-deoxyribose oxygen. A low pKa (i.e., 6.3) for Tyr-274 in the free enzyme is ruled out by NMR titration from pH 5.1 to 8.8 monitoring the C-zeta chemical shift of [zeta-13C]-tyrosine-enriched topoisomerase. The dependence of the internal equilibrium constant (Kcl) on pH reveals very similar pKa values as kcl (5.8 +/- 0.2 and 8.6 +/- 0.2). However, kr is found to be independent of pH. The differing response of kcl and kr to pH rules out a simple two-state internal cleavage equilibrium and suggests that a conformational change occurs following formation of the covalent complex which retains the correct protonation state for strand religation. A conformation step is further indicated by a 4.6-fold "thio effect" on kcl upon substitution of the nonbridging oxygen atom of the attacked phosphoryl group by sulfur [Stivers, J. T., Shuman, S., & Mildvan, A. S. (1994) Biochemistry 33, 327], and the absence of such an effect on kr, (krphos/krthio = 0.9 +/- 0.2), indicating the rates of cleavage and religation to be limited by covalent chemistry and a conformational step, respectively. The rate constant of this conformational change in the direction of religation agrees with the average rate constant for supercoil release from plasmid substrates, suggesting this conformational change to be a part of the topoisomerization step. Although the general acid and general base catalysts have not yet been identified, the quantitative roles of these and other residues in catalysis are discussed.
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PMID:Vaccinia DNA topoisomerase I: kinetic evidence for general acid-base catalysis and a conformational step. 780 9

Over the past ten years several laboratories have explored the use of perfluorochemical emulsions (PFCE) and carbogen (95% O2/5% CO2; C) or oxygen breathing as an adjuvant to radiation therapy and/or chemotherapy in solid tumor model systems. The rationale for the use of PFCE and C or oxygen breathing in this therapeutic setting is that solid tumor masses contain areas of hypoxia which are therapeutically resistant. Since x-rays and many chemotherapeutic agents require oxygen to be maximally cytotoxic and most normal tissues are well-oxygenated, the additional oxygen put in circulation by the PFCE/C should not increase the normal tissue toxicities produced by the various therapies. Several anticancer agents are dependent on oxygen to be cytotoxic, these drugs such as the iron-chelating peptide bleomycin are enhanced in antitumor activity by the co-administration of a PFCE/C. The antitumor alkylating agents especially cyclophosphamide, BCNU and melphalan show increased tumor cell killing without a concomitant increase in bone marrow toxicity when administered with PFCE/C. Enhanced activity was also observed when topoisomerase II inhibitors such as adriamycin and etoposide were co-administered with PFCE/C. Positive effects, although smaller, were observed when antimetabolites such as 5-fluorouracil and methotrexate were co-administered with PFCE/C.
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PMID:Combination of perfluorochemical emulsions and carbogen breathing with cancer chemotherapy. 784 13

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

This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6-fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC subline was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5-FU and topoisomerase II inhibitors; and (2) cross-resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT-diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT-diaphorase inhibitor dicumarol on the wild-type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti-oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC-induced DNA interstrand cross-linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.
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PMID:Characterization of a human bladder cancer cell line selected for resistance to mitomycin C. 807 54

Genetically determined chromosomal instability entails, among other sequelae, a condition of elevated cancer risk. Patients with the autosomal recessive disorder Fanconi's anemia (FA) often develop leukemias of the monocytic lineage together with pancytopenia, whereas the Bloom's syndrome (BS) mutation confers an early and elevated incidence of neoplasia of no particular type. Cultured cells from FA patients show spontaneously elevated rates of chromosome aberrations and a hypersensitivity to DNA cross-linking agents. Cytogenetic evaluation of cells from BS patients revealed elevated rates of sister chromatid exchanges, which were sensitive to the bromodeoxyuridine (BrdU) concentration used in the assay. Such a BrdU sensitivity was also found in cultured cells from healthy subjects exposed to the intracellular superoxide generator paraquat or to bleomycin. Skin fibroblasts from FA and BS patients show poor growth, which in the case of FA could be mitigated by lowering the oxygen concentration to 5%. Lymphoblastoid B-cell lines derived from peripheral blood samples from FA and BS patients show elevated numbers of cells arrested in the G2 phase of the cell cycle. This phenomenon could also be provoked by exposing cell lines from healthy subjects to compounds interfering with the function of DNA topoisomerase I (camptothecin) or II (m-AMSA). To test for a putative deficiency of either DNA topoisomerase, B-cell cultures from FA and BS patients were compared with cell cultures from healthy subjects regarding their sensitivity towards camptothecin and m-AMSA. No difference in sensitivity to these agents was found in patient vs. control cell lines, thus ruling out a deficiency in DNA topoisomerase I or II as the prime defect in these conditions of elevated cancer risk. The similarity between the cell cycle kinetic patterns found in untreated FA cell lines and in normal cell lines exposed to camptothecin or m-AMSA suggest that the DNA lesion in FA, presumably being caused by an oxygen-related mechanism, may interfere with DNA topoisomerase function.
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PMID:DNA topoisomerases and the DNA lesion in human genetic instability syndromes. 838 88

A variety of stimuli can induce cells to undergo apoptotic death. One of the most reproducible inducers is mild oxidative stress, be it via exposure to hydrogen peroxide, redox-cycling quinones or thiol-alkylating agents. Oxidative modifications of proteins and lipids have also been observed in cells undergoing apoptosis in response to non-oxidative stimuli such as glucocorticoids or topoisomerase II inhibitors. This suggests that some unidentified oxidative changes occur during apoptosis in many, if not all, cases. However, recent experiments demonstrating apparently normal apoptosis even when cells are cultured at low oxygen tensions show that reactive oxygen species cannot be essential mediators of this type of cell death. Experiments revealing that apoptosis is typically accompanied by a depletion of intracellular reduced glutathione (GSH) are also discussed. As GSH depletion will lower a cell's capacity to buffer against endogenous oxidants, we propose that it contributes to the increased oxidative damage commonly observed to accompany apoptosis. In addition, it may set a time limit on continued mitochondrial function (and thus indirectly on total ATP levels and membrane integrity) in apoptotic cells, and thereby explain the often observed 'secondary necrosis' of cells undergoing apoptosis in vitro.
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PMID:Signalling mechanisms and oxidative stress in apoptosis. 859 43

Human NK cells (with CD3-/56+ phenotype) acquired features characteristic of apoptosis after incubation with autologous monocytes, as revealed by apoptotic nuclear morphology, degradation of DNA into oligonucleosomal fragments, and reduced nuclear interchalation of propidium iodide. In contrast, T cells (CD3+/56-) remained non-apoptotic. The monocyte-induced apoptosis in NK cells was prevented by catalase, a scavenger of hydrogen peroxide; whereas superoxide dismutase (a scavenger of superoxide anion), hydroxyl radical scavengers such as mannitol and deferoxamine, or the hypochlorus acid scavenger taurine did not prevent apoptosis. Sodium azide, a myeloperoxidase inhibitor, substantially reduced the monocyte-induced apoptosis in NK cells. Exogenous hydrogen peroxide, at concentrations exceeding 1 microns, induced apoptosis in both NK and T cells. Apoptosis induced by hydrogen peroxide occurred independently of synthesis of protein or mRNA and was blocked by the endonuclease inhibitor aurin tricarboxylic acid. Furthermore, oxidatively induced apoptosis in NK cells was inhibited by herbimycin A, indicating that apoptosis was dependent on protein kinases. Two to five times more hydrogen peroxide was required to induce apoptosis in T cells compared with NK cells. Similarly, NK cells were considerably more susceptible to apoptosis induced by the topoisomerase II inhibitor etoposide or by gamma-irradiation than were T cells. We conclude that monocyte-derived reactive oxygen metabolites kill NK cells by apoptosis and that NK cells are unusually sensitive to oxidatively as well as non-oxidatively induced apoptosis.
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PMID:Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. 859 91

There is compelling evidence for the central role of oxidative damage in the aging process and for the participation of reactive oxygen species in tumor initiation and promotion. Caloric restriction (CR) or energy restriction retards age-associated increases in mitochondrial free-radical production and reduces the accumulation of oxidatively damaged cell components. CR has also been shown to slow down age-related declines in various repair capabilities, including some types of DNA repair. It is proposed that inhibitors of mitochondrial electron transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal, amiodarone, valinomycin, etc.), when used at extremely low doses, could mimic the effects of CR in model systems. The objective is to lower mitochondrial free-radical production by decreasing the fraction of electron carriers in the reduced state. In addition to a variety of other effects, CR has been shown to increase the rate of apoptosis, particularly in preneoplastic cells, and in general, to promote elevated levels of free glucocorticoids (GCs). GCs are known to induce tissue-specific apoptosis and to upregulate gap-junction-mediated intercellular communication (GJIC). Tumor promoters like phorbol esters have the opposite effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme poly (ADP-ribose) polymerase (PARP) is thought to play a central role in apoptosis, in a manner that has been highly conserved in evolution. There is good evidence that the apoptosis-associated Ca/Mg-dependent DNA endonuclease is maintained in a latent form by being poly (ADP-ribosylated). Apoptosis would require the removal of this polymer from the endonuclease, and, most likely, its removal from topoisomerase II and histone H1 as well. The role of poly (ADP-ribose) in apoptosis, carcinogenesis, and aging could be studied by the use of modulators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethanol, etc.), inhibitors of poly ADP-ribose) glycohydrolase activity (ethacridine, 43 degrees C, etc.), and inhibitors of the PARP-specific protease (interleukin-1 beta converting enzyme (ICE)-like protease). Also, it would be of interest to determine if CR can decrease the half-life of poly (ADP-ribose), upregulate GJIC, and modulate the activities of PARP, the glycohydrolase, and the PARP-specific protease, factors potentially important in these processes.
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PMID:The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. 865 88


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