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)

9-beta-D-arabinofuranosylguanine (Ara-G) is an important and relatively new guanosiue analog with activity in patients with T-cell malignancies. The biochemical and molecular events leading to resistance to Ara-G are not fully understood. Therefore we generated two Ara-G-resistant human MOLT-4 leukemic cell lines with different levels of resistance. The mitochondrial enzyme deoxyguanosine kinase (dGK) and the nuclear/cytosol enzyme deoxycytidine kinase (dCK) are key enzymes in the activation of Ara-G. Decreased levels of dGK protein and mRNA were found in both resistant cell sublines. The activity of dCK was decreased in the subline with higher resistance to Ara-G and these cells were highly cross-resistant to other nucleosides activated by dCK. Increased activity of the mitochondrial enzyme thymidine kinase 2 was observed in both resistant sublines and this could be related to the dGK deficiency. In search for other resistance mechanisms it was found that the resistant cells overexpress the mdr1 gene, while no changes were detected in the levels of multidrug resistance-associated protein 1 through 6, lung resistance-associated protein or topoisomerase IIalpha or IIbeta. Taken together, our findings demonstrate that multiple mechanisms are involved in the acquired resistance to Ara-G. However, low expression of dGK is the most apparent alteration in both resistant cell lines. Partial deficiency of dCK was found in the subline cells with higher resistance to Ara-G. Furthermore, Ara-G may select for high expression of the multidrug resistance (mdr1) which could be a specific resistance mechanism but more likely part of an overall cellular stress response.
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PMID:Low level of mitochondrial deoxyguanosine kinase is the dominant factor in acquired resistance to 9-beta-D-arabinofuranosylguanine cytotoxicity. 1205 84

In a previous report, we discussed an extract from a marine red alga, Amphiroa zonata, which shows selective cytotoxic activity to human leukemic cells, but no cytotoxicity to normal human dermal fibroblast (HDF) cells in vitro. In this study, we identified palmitic acid, a selective cytotoxic substance from the marine algal extract, and investigated its biological activities. At concentrations ranging from 12.5 to 50 micrograms/ml, palmitic acid shows selective cytotoxicity to human leukemic cells, but no cytotoxicity to normal HDF cells. Furthermore, palmitic acid induces apoptosis in the human leukemic cell line MOLT-4 at 50 micrograms/ml. Palmitic acid also shows in vivo antitumor activity in mice. One molecular target of palmitic acid in tumor cells is DNA topoisomerase I, however, interestingly, it does not affect DNA topoisomerase II, suggesting that palmitic acid may be a lead compound of anticancer drugs.
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PMID:Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga. 1252 68

Two cell lines which show different patterns of DNA fragmentation have been examined for variations of their nuclear morphology during apoptosis. FDCP-Mix, a pluripotent murine haemopoietic stem cell line which undergoes typical internucleosomal cleavage of DNA when induced to apoptosis either by drugs or withdrawal of growth factor (IL-3) was compared with the human lymphoid leukemia cell line MOLT-4, a cell line which undergoes apoptosis without production of a typical DNA 'ladder'. The nuclear morphology of FDCP-Mix cells was consistent after apoptotic induction by drug or by growth factor withdrawal. Apoptotic nuclear morphology for MOLT-4 and FDCP-Mix showed variations in the distribution, density and texture of the electron dense nuclear marginations. Despite these differences, clustering of nuclear pore complexes (NPCs) after treatment with the topoisomerase II inhibitor etoposide was a common phenomenon for both cell lines. Moreover, pore clustering for FDCP-Mix nuclei occurred independently from the way in which apoptosis was induced, either by growth factor withdrawal or etoposide treatment. In a novel approach, we visualised the clustering of NPCs three-dimensionally by field emission in-lens scanning electron microscopy (FEISEM).
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PMID:Nuclear pore clustering is a consistent feature of apoptosis in vitro. 1718 65

Topoisomerase IIalpha is known to be critically involved in both cell proliferation and cell death. The mechanisms responsible for stress-dependent topoisomerase IIalpha alterations, however, remain unclear. This study focused on the behavior of topoisomerase IIalpha in response to oxidative stress induced by hydrogen peroxide (H(2)O(2)). The catalytic activity of topoisomerase IIalpha in MOLT-4 cells treated with H(2)O(2) decreased in parallel with the alteration of topoisomerase IIalpha expression. The ubiquitination of topoisomerase IIalpha was dependent on oxidative stress. BRCA1, a tumor-suppressor gene, appeared to be involved in these alterations in topoisomerase IIalpha. Furthermore, the retinoblastoma protein (pRb) was required for the ubiquitination of topoisomerase IIalpha by BRCA1. We conclude that the functions of topoisomerase IIalpha are regulated by ubiquitination on exposure to oxidative stress.
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PMID:BRCA1-mediated ubiquitination inhibits topoisomerase II alpha activity in response to oxidative stress. 1816 55

Cyclins B (B1) and E, integral components of the cell cycle drive machinery consisting of p34cdc2 and p33cdk2 cyclin-dependent kinases and their regulatory kinases and phosphatases, were detected in human leukemic MOLT-4 cells and in mitogen-stimulated normal peripheral blood lymphocytes immunocytochemically, using commercially available antibodies. Flow cytometric bivariate analysis of DNA content and cyclin B or E made it possible to correlate expression of these proteins in individual cells with their position in the cycle, without the necessity for cell synchronization. In both cell systems, cyclin B was expressed almost exclusively in G2 and M cells: cells in G1 and throughout most of S phase, were negative. Cells arrested in G2 by gamma radiation or the DNA topoisomerase II inhibitor m-AMSA for up to 4 h, had very high levels of cyclin B. Cells arrested in metaphase by vinblastine also strongly expressed cyclin B, although to a lesser degree than cells arrested in G2. Expression of cyclin E was maximal in late G1 and in early S, while its expression progressively decreased during the remainder of S phase. Two compartments of the G1 phase, G1A and G1B representing cells that were cyclin E negative and positive, respectively, were discriminated. The kinetics of cell exit from G1A, under conditions of stathmokinesis induced by vinblastine, showed a stochastic component; the half-time of MOLT-4 cell residence in G1A was 5.6 h. Nonstimulated (G0) lymphocytes did not express cyclin E; their stimulation by phytohemagglutinin led to the appearance of a subpopulation of cyclin E positive cells as early as 18 h after addition of the mitogen. Maximal expression of cyclin E occurred in G1 lymphocytes just prior to cell entrance to S, and in early S phase cells. Thus, expression of cyclin E can be used as a marker of lymphocyte stimulation (G0 to G1 transition). The combined use of cyclin B and E antibodies can identify late G1, S and G2+M cells, and thus it may be applied to measure the fraction of cycling cells in cell populations, e.g. the tumor growth fraction.
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PMID:Expression of cyclins-B and cyclins-e in individual molt-4 cells and in stimulated human-lymphocytes during their progression through the cell-cycle. 2157 69

The isoquinoline sulfonamide (H7) is an inhibitor of protein kinase C (PKC) that also inhibits the activity of cyclic nucleotide-dependent protein kinases. The effect of H7 on mitogen stimulation (G0 to G1 transition) of normal human lymphocytes and on their subsequent progression through the cell cycle was investigated and compared with the effect of this inhibitor on proliferation of human lymphocytic leukemic MOLT-4 cells. At H7 concentrations of 10 and 50 muM, the transition of G0 lymphocytes to the cell cycle was suppressed by 45 and 98%, respectively. The cell cycle progression of stimulated lymphocytes was unaffected at 10 muM H7, whereas, at 50 muM, the overall rate of progression was reduced by 50% with no evidence of cell arrest at a specific phase of the cycle. Similar concentrations of H7 (45 muM) suppressed proliferation of MOLT-4 cells by 50%, though, in the latter case, cells underwent transition to higher DNA ploidy, most likely via endoreduplication. Thus, the G0 to G1 transition appears to be the event most sensitive to H7. Exposure of MOLT-4 cells to 100 muM H7 for 24 h induced extensive apoptosis: activation of an endogenous nuclease with preference to internucleosomal linker DNA sections resulted in DNA degradation (revealed by agarose gel electrophoresis and loss of DNA measured by flow cytometry), which was paralleled by intracellular proteolysis, while the integrity of the plasma membrane, mitochondria and lysosomes was preserved. Morphological examination of these apoptotic cells confirmed DNA degradation. However, the perinuclear and fine-granular localization of the remaining DNA and lack of typical chromatin condensation and nuclear fragmentation differed from the classical pattern of apoptosis observed in other cell systems, suggesting that some events of apoptosis (nuclear fragmentation) may be affected by H7. The observed effects are consistent with the possible role of H7 in inhibition of PKC or its direct effect on the ATP-binding domain of DNA topoisomerase II, which shares homology with the H7 binding sites on PKC and the cyclic nucleotide-dependent protein kinases.
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PMID:The protein-kinase-C inhibitor h7 blocks normal human lymphocyte stimulation and induces apoptosis of both normal lymphocytes and leukemia molt-4 cells. 2157 14

Antitumour chemotherapy is nowadays a very active field of research, DNA targeting drugs being the most widely used group in therapy. The design, synthesis and anticancer activity of a new class of anticancer derivatives with pyrrolo-1,2-diazine and benzoquinone skeleton is presented. The synthesis is direct and efficient, involving an alkylation followed by a [3+2] dipolar cycloaddition. The penta- and tetra-cyclic pyrrolo-1,2-diazine were evaluated for their in vitro anticancer activity against an NCI 60 human tumour cell line panel. The pentacyclic-1,2-diazine exhibit a significant anticancer activity against Non-Small Cell Lung Cancer NCI-H460, Leukemia MOLT-4, Leukemia CCRF-CEM and Breast Cancer MCF7. We hypothesize that these molecules will exert their anticancer activity through multiple mechanisms of action: intercalating the DNA, inhibiting the topoisomerase enzymes and, destroying the DNA strands via electron transfer mechanism. However, the intercalation with the DNA seems to prevail in competition with the others mechanisms.
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PMID:Hybrid anticancer 1,2-diazine derivatives with multiple mechanism of action. Part 3. 2423 42

DNA topoisomerase II inhibitors e.g. doxorubicin and etoposide are currently used in the chemotherapy for acute lymphoblastic leukemia (ALL). These inhibitors have serious side effects during the chemotherapy e.g. cardiotoxicity and secondary malignancies. In this study we show that sulfonoquinovosyl diacylglyceride (SQDG) isolated from Azadirachta indica exerts potent anti-ALL activity both in vitro and in vivo in nude mice and it synergizes with doxorubicin and etoposide. SQDG selectively targets ALL MOLT-4 cells by inhibiting catalytic activity of topoisomerase I enzyme and inducing p53 dependent apoptotic pathway. SQDG treatment induces recruitment of ATR at chromatin and arrests the cells in S-phase. Down-regulation of topoisomerase I or p53 renders the cells less sensitive for SQDG, while ectopic expression of wild type p53 protein in p53 deficient K562 cells results in chemosensitization of the cells for SQDG. We also show that constant ratio combinations of SQDG and etoposide or SDQG and doxorubicin exert synergistic effects on MOLT-4 cell killing. This study suggests that doses of etoposide/doxorubicin can be substantially reduced by combining SQDG with these agents during ALL chemotherapy and side effects caused can be minimized. Thus dual targeting of topoisomerase I and II enzymes is a promising strategy for improving ALL chemotherapy.
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PMID:Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo. 2618 12

Quinalizarin (THAQ), a hydroxy-9,10-anthraquinone analogue of the family of anthracycline anticancer drugs and an inhibitor of protein kinase, was observed for its anticancer activity. Because apart from showing anticancer activity, anthracyclines and their analogues also show cardiotoxic side effects, believed to be addressed through metal complex formation; an effort was made to realize this by preparing a Co^II complex of THAQ. The aim of this study was to find out if complex formation leads to a decrease in the generation of intermediates that are responsible for toxic side effects. However, because this also meant that efficacy on cancer cells would be compromised, studies were undertaken on two cancer cell lines, namely, acute lymphoblastic leukemia (ALL) MOLT-4 and HCT116 cells. The complex decreases the flow of electrons from NADH to molecular oxygen (O₂) in the presence of NADH dehydrogenase forming less semiquinone than THAQ. It showed increased affinity toward DNA with binding constant values remaining constant over the physiological pH range unlike THAQ (for which decrease in binding constant values with increase in pH was observed). The complex is probably a human DNA topoisomerase I and human DNA topoisomerase II poison acting by stabilizing the covalent topoisomerase-cleaved DNA adduct, a phenomenon not observed for THAQ. Activity of the compounds on cancer cells suggests that THAQ was more effective on ALL MOLT-4 cells, whereas the complex performed better on HCT116 cells. Results suggest that the formation of semiquinone probably dominates the action because of THAQ, whereas the performance of the complex is attributed to increased DNA binding, inhibition of topoisomerase, and so forth. Inspite of a decrease in the generation of superoxide by the complex, it did not hamper efficacy on either cell line, probably compensated by improved DNA binding and inhibition of topoisomerase enzymes which are positive attributes of complex formation. A decrease in superoxide formation suggests that the complex could be less cardiotoxic, thus increasing its therapeutic index.
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PMID:Activity of Co^II-Quinalizarin: A Novel Analogue of Anthracycline-Based Anticancer Agents Targets Human DNA Topoisomerase, Whereas Quinalizarin Itself Acts via Formation of Semiquinone on Acute Lymphoblastic Leukemia MOLT-4 and HCT 116 Cells. 3145 55


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