Journal articles: 'DNA topoisomerases; Cell growth'

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Levin, N. A., M. A. Bjornsti, and G. R. Fink. "A novel mutation in DNA topoisomerase I of yeast causes DNA damage and RAD9-dependent cell cycle arrest." Genetics 133, no. 4 (April 1, 1993): 799–814. http://dx.doi.org/10.1093/genetics/133.4.799.

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Abstract DNA topoisomerases, enzymes that alter the superhelicity of DNA, have been implicated in such critical cellular functions as transcription, DNA replication, and recombination. In the yeast Saccharomyces cerevisiae, a null mutation in the gene encoding topoisomerase I (TOP1) causes elevated levels of mitotic recombination in the ribosomal DNA (rDNA), but has little effect on growth. We have isolated a missense mutation in TOP1 that causes mitotic hyper-recombination not only in the rDNA, but also at other loci, in addition to causing a number of other unexpected phenotypes. This topoisomerase I mutation (top1-103) causes slow growth, constitutive expression of DNA damage-inducible genes, and inviability in the absence of the double-strand break repair system. Overexpression of top1-103 causes RAD9-dependent cell cycle arrest in G2. We show that the Top1-103 enzyme nicks DNA in vitro, suggesting that it damages DNA directly. We propose that Top1-103 mimics the action of wild-type topoisomerase I in the presence of the anti-tumor drug, camptothecin.

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Treshalin, Michael I., and E. V. Neborak. "TOPOISOMERASES: FEATURES OF THE ACTION, CLASSIFICATION, CELL FUNCTIONS, INHIBITION, ANTHRAFURANDION." Russian Journal of Oncology 23, no. 2 (April 15, 2018): 60–70. http://dx.doi.org/10.18821/1028-9984-2018-23-2-60-70.

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Introduction. Topoisomerases influence on DNA topology and are capable of running down their super spiraling molecules by importation of one- or two-chained ruptures with the subsequent restitution and also the negative super rounds or catenae’s. Topoisomerases are known to be targets for antineoplastic therapy. Inhibitors of these enzymes of various nature and chemical structure are widely used for the suppression of tumor Topoisomerase I and/or II activity with the blocking cells in the phase G2 and a delay of their introduction in mitosis. Such difficult curable tumors as colorectal cancer, carcinoma of the stomach, non-small cell lung cancer and so forth are the most sensitive to these drugs. The search of perspective antineoplastic inhibitors is implemented generally in ranks of the non-camptothecin agents among which heterocyclic condensed nitrogenous compounds, in particular, anthrafurandiones show the most significant results. The review of thematic literature from 2011 to 2018 is devoted to the description of properties of topoisomerase as targets and their inhibitors from perspective classes. Objectives: 1. The analysis of signal characteristics of topoisomerases as targets for anticancer non-camptothecin inhibitors. 2. Identification of structure-activity relationship in the ranks of potential inhibitors of topoisomerases. 3. The choice of the most perspective non-camptothecin topoisomerase inhibitors among heterocyclic condensed nitrogenous compounds on the basis of the comparative analysis of structure and properties. Material and methods. Materials of 79 scientific articles published in the leading biological, biochemical and chemical journals of the different countries within the 8 last years are subjected to the analysis. The structure of the review meets the purpose and tasks of the scientific analysis. Results. The analysis of the thematic literature showed topoisomerases to be relevant targets for antineoplastic therapy of severe oncological pathology. In this regard, intensive search of various pharmaceuticals among topoisomerase inhibitors is performed in recent years. Researchers modify the known basic structures as well as synthesize new compounds. The discovery of a top-directional effect of the known medicines expands the data on their mechanism of the action. To identify the topoisomerase inhibitory activity of the drug the methods with the use of plasmid DNA is applied. The cytotoxic activity, apoptosis induction, including the caspases activation, modification of mitochondrial potential, influence on p53 and others are examined in parallel studies. The research directed on the identification of new effective non-camptothecin oral topoisomerase inhibitors among the anthracyclines derivatives are of undoubted relevance. Such agents, in contrast to Doxorubicin (anthracycline antibiotic widely used for tumor therapy), have moderate toxicity and allow to control the growth of solid tumors and leukemia in mono-therapy mode. Conclusion. In terms of searching of original antineoplastic agents, a class of heterocyclic condensed nitrogenous compounds, first of all, the anthraquinones showing properties of topoisomerase inhibitors is one of the most promising. The results of chemical and biological research of the compounds of this series were laid in a basis of the design of medicinal substances and their drug formulations. Prognostically significant data obtained in preclinical testing allow us to hope that obtained antitumor agents will be highly effective on a clinical stage of trials.

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Pereira, Michelle X. G., Amanda S. O. Hammes, Flavia C. Vasconcelos, Aline R. Pozzo, Thaís H. Pereira, Ernesto R. Caffarena, Cerli R. Gattass, and Raquel C. Maia. "Antitumor Effect of Pomolic Acid in Acute Myeloid Leukemia Cells Involves Cell Death, Decreased Cell Growth and Topoisomerases Inhibition." Anti-Cancer Agents in Medicinal Chemistry 18, no. 10 (January 23, 2019): 1457–68. http://dx.doi.org/10.2174/1871520618666180412120128.

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Background: Acute myeloid leukemia (AML) represents the largest number of annual deaths from hematologic malignancy. In the United States, it was estimated that 21.380 individuals would be diagnosed with AML and 49.5% of patients would die in 2017. Therefore, the search for novel compounds capable of increasing the overall survival rate to the treatment of AML cells is urgent. Objectives: To investigate the cytotoxicity effect of the natural compound pomolic acid (PA) and to explore the mechanism of action of PA in AML cell lines with different phenotypes. Methods: Three different AML cell lines, HL60, U937 and Kasumi-1 cells with different mechanisms of resistance were used to analyze the effect of PA on the cell cycle progression, on DNA intercalation and on human DNA topoisomerases (hTopo I and IIα) in vitro studies. Theoretical experiments of the inhibition of hTopo I and IIα were done to explore the binding modes of PA. Results: PA reduced cell viability, induced cell death, increased sub-G0/G1 accumulation and activated caspases pathway in all cell lines, altered the cell cycle distribution and inhibited the catalytic activity of both human DNA topoisomerases. Conclusion: Finally, this study showed that PA has powerful antitumor activity against AML cells, suggesting that this natural compound might be a potent antineoplastic agent to improve the treatment scheme of this neoplasm.

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Drlica, K., and X. Zhao. "DNA gyrase, topoisomerase IV, and the 4-quinolones." Microbiology and Molecular Biology Reviews 61, no. 3 (September 1997): 377–92. http://dx.doi.org/10.1128/mmbr.61.3.377-392.1997.

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For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog of gyrase, topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, topoisomerase IV is a target of the 4-quinolones, antibacterial agents that had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of quinolone arises from mutation of the gyrase A protein and resistance to high levels of quinolone arises from mutation of a second gyrase and/or topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.

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Singh, Swati, Veda P. Pandey, Kusum Yadav, Anurag Yadav, and U. N. Dwivedi. "Natural Products as Anti-Cancerous Therapeutic Molecules Targeted towards Topoisomerases." Current Protein & Peptide Science 21, no. 11 (December 31, 2020): 1103–42. http://dx.doi.org/10.2174/1389203721666200918152511.

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: Topoisomerases are reported to resolve the topological problems of DNA during several cellular processes, such as DNA replication, transcription, recombination, and chromatin remodeling. Two types of topoisomerases (Topo I and II) accomplish their designated tasks by introducing single- or double-strand breaks within the duplex DNA molecules, and thus maintain the proper structural conditions of DNA to release the topological torsions, which is generated by unwinding of DNA to access coded information, in the course of replication, transcription, and other processes. Both the topoisomerases have been looked at as crucial targets against various types of cancers such as lung, melanoma, breast, and prostate cancers. Conceptually, targeting topoisomerases will disrupt both DNA replication and transcription, thereby leading to inhibition of cell division and consequently stopping the growth of actively dividing cancerous cells. Since the discovery of camptothecin (an alkaloid) as an inhibitor of Topo I in 1958, a number of derivatives of camptothecin were developed as potent inhibitors of Topo I. Two such derivatives of camptothecin, namely, topotecan and irinotecan, have been commonly used as US Food and Drug Administration (FDA) approved drugs against Topo I. Similarly, the first Topo II inhibitor, namely, etoposide, an analogue of podophyllotoxin, was developed in 1966 and got FDA approval as an anti-cancer drug in 1983. Subsequently, several other inhibitors of Topo II, such as doxorubicin, mitoxantrone, and teniposide, were developed. These drugs have been reported to cause accumulation of cytotoxic non-reversible DNA double-strand breaks (cleavable complex). Thus, the present review describes the anticancer potential of plant-derived secondary metabolites belonging to alkaloids, flavonoids and terpenoids directed against topoisomerases. Furthermore, in view of the recent advances made in the field of computer-aided drug design, the present review also discusses the use of computational approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to assess and predict the safety, efficacy, potency and identification of these potent anti-cancerous therapeutic molecules.

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Bailis, A. M., L. Arthur, and R. Rothstein. "Genome rearrangement in top3 mutants of Saccharomyces cerevisiae requires a functional RAD1 excision repair gene." Molecular and Cellular Biology 12, no. 11 (November 1992): 4988–93. http://dx.doi.org/10.1128/mcb.12.11.4988-4993.1992.

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Saccharomyces cerevisiae cells that are mutated at TOP3, a gene that encodes a protein homologous to bacterial type I topoisomerases, have a variety of defects, including reduced growth rate, altered gene expression, blocked sporulation, and elevated rates of mitotic recombination at several loci. The rate of ectopic recombination between two unlinked, homologous loci, SAM1 and SAM2, is sixfold higher in cells containing a top3 null mutation than in wild-type cells. Mutations in either of the two other known topoisomerase genes in S. cerevisiae, TOP1 and TOP2, do not affect the rate of recombination between the SAM genes. The top3 mutation also changes the distribution of recombination events between the SAM genes, leading to the appearance of novel deletion-insertion events in which conversion tracts extend beyond the coding sequence, replacing the DNA flanking the 3' end of one SAM gene with nonhomologous DNA flanking the 3' end of the other. The effects of the top3 null mutation on recombination are dependent on the presence of an intact RAD1 excision repair gene, because both the rate of SAM ectopic gene conversion and the conversion tract length were reduced in rad1 top3 mutant cells compared with top3 mutants. These results suggest that a RAD1-dependent function is involved in the processing of damaged DNA that results from the loss of Top3 activity, targeting such DNA for repair by recombination.

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Umemura, Ken, Kae Yanase, Mitsue Suzuki, Koichi Okutani, Takao Yamori, and Toshiwo Andoh. "Inhibition of DNA topoisomerases I and II, and growth inhibition of human cancer cell lines by a marine microalgal polysaccharide." Biochemical Pharmacology 66, no. 3 (August 2003): 481–87. http://dx.doi.org/10.1016/s0006-2952(03)00281-8.

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Avemann, K., R. Knippers, T. Koller, and J. M. Sogo. "Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks." Molecular and Cellular Biology 8, no. 8 (August 1988): 3026–34. http://dx.doi.org/10.1128/mcb.8.8.3026-3034.1988.

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The structure of replicating simian virus 40 minichromosomes, extracted from camptothecin-treated infected cells, was investigated by biochemical and electron microscopic methods. We found that camptothecin frequently induced breaks at replication forks close to the replicative growth points. Replication branches were disrupted at about equal frequencies at the leading and the lagging strand sides of the fork. Since camptothecin is known to be a specific inhibitor of type I DNA topoisomerase, we suggest that this enzyme is acting very near the replication forks. This conclusion was supported by experiments with aphidicolin, a drug that blocks replicative fork movement, but did not prevent the camptothecin-induced breakage of replication forks. The drug teniposide, an inhibitor of type II DNA topoisomerase, had only minor effects on the structure of these replicative intermediates.

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Saijo, Masafumi, Michio Ui, and Takemi Enomoto. "Growth state and cell cycle dependent phosphorylation of DNA topoisomerase II in Swiss 3T3 cells." Biochemistry 31, no. 2 (January 21, 1992): 359–63. http://dx.doi.org/10.1021/bi00117a007.

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Hisatomi, Takashi, Naoko Sueoka-Aragane, Akemi Sato, Rika Tomimasu, Masaru Ide, Akihiro Kurimasa, Kazuya Okamoto, Shinya Kimura, and Eisaburo Sueoka. "NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase." Blood 117, no. 13 (March 31, 2011): 3575–84. http://dx.doi.org/10.1182/blood-2010-02-270439.

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Abstract Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease, incurable by standard chemotherapy. NK314, a new anticancer agent possessing inhibitory activity specific for topoisomerase IIα (Top2α), inhibited the growth of various ATL cell lines (50% inhibitory concentration: 23-70nM) with more potent activity than that of etoposide. In addition to the induction of DNA double-strand breaks by inhibition of Top2α, NK314 induced degradation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), resulting in impaired DNA double-strand break repair. The contribution of DNA-PK to inhibition of cell growth was affirmed by the following results: NK314 inhibited cell growth of M059J (a DNA-PKcs–deficient cell line) and M059K (a cell line with DNA-PKcs present) with the same potency, whereas etoposide exhibited weak inhibition of cell growth with M059K cells. A DNA-PK specific inhibitor, NU7026, enhanced inhibitory activity of etoposide on M059K as well as on ATL cells. These results suggest that NK314 is a dual inhibitor of Top2α and DNA-PK. Because ATL cells express a high amount of DNA-PKcs, NK314 as a dual molecular targeting anticancer agent is a potential therapeutic tool for treatment of ATL.

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Maschera, B., E. Ferrazzi, M. Rassu, M. Toni, and G. Palù. "Evaluation of Topoisomerase Inhibitors as Potential Antiviral Agents." Antiviral Chemistry and Chemotherapy 4, no. 2 (April 1993): 85–91. http://dx.doi.org/10.1177/095632029300400202.

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Anti-eukaryotic topoisomerase drugs, Camptothecin and Etoposide, were tested for their ability of selectively interfering with the replication of simian virus 40 (SV40) DNA. Nalidixic acid was also assayed for a comparison, since the compound has been previously reported to affect papoyavirus growth. Our results indicate that anti-eukaryotic topoisomerase drugs significantly inhibit viral DNA replication but at concentrations that are also toxic for uninfected cells. Etoposide treatment produced a relatively higher number of DNA-protein cross-links in virus-infected cells as compared to uninfected control cells. Nalidixic acid displayed some degree of selectivity for inhibiting SV40 DNA synthesis more effectively than synthesis of cellular DNA without appreciable reduction of cell growth. This activity does not appear to depend on DNA damage or interference with topoisomerase II and deserves further evaluation.

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Aoyama, Masako, Dale R. Grabowski, Richard J. Isaacs, Kim A. Krivacic, Lisa A. Rybicki, Ronald M. Bukowski, Mahrukh K. Ganapathi, Ian D. Hickson, and Ram Ganapathi. "Altered Expression and Activity of Topoisomerases During All-Trans Retinoic Acid-Induced Differentiation of HL-60 Cells." Blood 92, no. 8 (October 15, 1998): 2863–70. http://dx.doi.org/10.1182/blood.v92.8.2863.

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Abstract Regulation of topoisomerase II (TOPO II) isozymes  and β is influenced by the growth and transformation state of cells. Using HL-60 cells induced to differentiate by all-trans retinoic acid (RA), we have investigated the expression and regulation of TOPO II isozymes as well as the levels of topoisomerase I (TOPO I). During RA-induced differentiation of human leukemia HL-60 cells, levels of TOPO I remained unchanged, whereas the levels and phosphorylation of TOPO II and TOPO IIβ proteins were increased twofold to fourfold and fourfold to eightfold, respectively. The elevation of TOPO II ( and β) protein levels and phosphorylation was apparent at 48 hours of treatment with RA and persisted through 96 hours. The increased level of TOPO IIβ protein was also detected in differentiated cells subsequently cultured for 96 hours in RA-free medium. Pulse chase experiments in cells labeled with 35S-methionine showed that the rate of degradation of TOPO IIβ protein in control cells was about twofold faster than that in the differentiated RA-treated cells. The level of decatenation activity of kDNA was comparable in nuclear extracts from control or RA-treated cells. Whereas etoposide (1 to 10 μmol/L) -induced DNA cleavage was not significantly different, apoptosis was significantly lower (P = .012) in RA-treated versus control cells after exposure to 10 μmol/L etoposide. Consistent with unaltered levels of TOPO I, camptothecin (CPT) -induced DNA cleavage was similar in control or RA-treated cells. However, apoptosis after exposure to 1 to 10 μmol/L CPT was significantly lower (P = .003 to P < .001) in RA-treated versus control cells. Results suggest that TOPO IIβ protein levels are posttranscriptionally regulated and that degradation of TOPO IIβ is decreased during RA-induced differentiation. Furthermore, whereas the total level of TOPO II ( + β) is increased with RA, the level of TOPO II catalytic activity and etoposide-stabilized DNA cleavage activity remains unaltered. Thus, TOPO IIβ may have a specific role in transcription of genes involved in differentiation with RA treatment. © 1998 by The American Society of Hematology.

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Aoyama, Masako, Dale R. Grabowski, Richard J. Isaacs, Kim A. Krivacic, Lisa A. Rybicki, Ronald M. Bukowski, Mahrukh K. Ganapathi, Ian D. Hickson, and Ram Ganapathi. "Altered Expression and Activity of Topoisomerases During All-Trans Retinoic Acid-Induced Differentiation of HL-60 Cells." Blood 92, no. 8 (October 15, 1998): 2863–70. http://dx.doi.org/10.1182/blood.v92.8.2863.420k20_2863_2870.

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Regulation of topoisomerase II (TOPO II) isozymes  and β is influenced by the growth and transformation state of cells. Using HL-60 cells induced to differentiate by all-trans retinoic acid (RA), we have investigated the expression and regulation of TOPO II isozymes as well as the levels of topoisomerase I (TOPO I). During RA-induced differentiation of human leukemia HL-60 cells, levels of TOPO I remained unchanged, whereas the levels and phosphorylation of TOPO II and TOPO IIβ proteins were increased twofold to fourfold and fourfold to eightfold, respectively. The elevation of TOPO II ( and β) protein levels and phosphorylation was apparent at 48 hours of treatment with RA and persisted through 96 hours. The increased level of TOPO IIβ protein was also detected in differentiated cells subsequently cultured for 96 hours in RA-free medium. Pulse chase experiments in cells labeled with 35S-methionine showed that the rate of degradation of TOPO IIβ protein in control cells was about twofold faster than that in the differentiated RA-treated cells. The level of decatenation activity of kDNA was comparable in nuclear extracts from control or RA-treated cells. Whereas etoposide (1 to 10 μmol/L) -induced DNA cleavage was not significantly different, apoptosis was significantly lower (P = .012) in RA-treated versus control cells after exposure to 10 μmol/L etoposide. Consistent with unaltered levels of TOPO I, camptothecin (CPT) -induced DNA cleavage was similar in control or RA-treated cells. However, apoptosis after exposure to 1 to 10 μmol/L CPT was significantly lower (P = .003 to P < .001) in RA-treated versus control cells. Results suggest that TOPO IIβ protein levels are posttranscriptionally regulated and that degradation of TOPO IIβ is decreased during RA-induced differentiation. Furthermore, whereas the total level of TOPO II ( + β) is increased with RA, the level of TOPO II catalytic activity and etoposide-stabilized DNA cleavage activity remains unaltered. Thus, TOPO IIβ may have a specific role in transcription of genes involved in differentiation with RA treatment. © 1998 by The American Society of Hematology.

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Gangloff, S., J. P. McDonald, C. Bendixen, L. Arthur, and R. Rothstein. "The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase." Molecular and Cellular Biology 14, no. 12 (December 1994): 8391–98. http://dx.doi.org/10.1128/mcb.14.12.8391-8398.1994.

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We have previously shown that cells mutant for TOP3, a gene encoding a prokaryotic-like type I topoisomerase in Saccharomyces cerevisiae, display a pleiotropic phenotype including slow growth and genome instability. We identified a mutation, sgs1 (slow growth suppressor), that suppresses both the growth defect and the increased genomic instability of top3 mutants. Here we report the independent isolation of the SGS1 gene in a screen for proteins that interact with Top3. DNA sequence analysis reveals that the putative Sgs1 protein is highly homologous to the helicase encoded by the Escherichia coli recQ gene. These results imply that Sgs1 creates a deleterious topological substrate that Top3 preferentially resolves. The interaction of the Sgs1 helicase homolog and the Top3 topoisomerase is reminiscent of the recently described structure of reverse gyrase from Sulfolobus acidocaldarius, in which a type I DNA topoisomerase and a helicase-like domain are fused in a single polypeptide.

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Janočková, Jana, Jana Plšíková, Jana Kašpárková, Viktor Brabec, Rastislav Jendželovský, Jaromír Mikeš, Ján Kovaľ, et al. "Inhibition of DNA topoisomerases I and II and growth inhibition of HL-60 cells by novel acridine-based compounds." European Journal of Pharmaceutical Sciences 76 (August 2015): 192–202. http://dx.doi.org/10.1016/j.ejps.2015.04.023.

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Renis, Marcella, Laura Calandra, Christian Scifo, Barbara Tomasello, Venera Cardile, Luca Vanella, Roberto Bei, Luca La Fauci, and Fabio Galvano. "Response of cell cycle/stress-related protein expression and DNA damage upon treatment of CaCo2 cells with anthocyanins." British Journal of Nutrition 100, no. 1 (July 2008): 27–35. http://dx.doi.org/10.1017/s0007114507876239.

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Anthocyanins are a class of flavonoids, widely spread throughout the plant kingdom, exhibiting important antioxidant and anti-inflammatory actions as well as chemotherapeutic effects; nonetheless, little is known about the molecular mechanisms by which these activities are exerted. The present study is aimed at investigating molecular mechanisms involved in the chemotherapeutic effects induced by both cyanidin-3-O-β glucopyranoside (CY3G) and its aglycon form, cyanidin chloride (CY), in human colon cancer cells (CaCo2). The effect on cell growth, reactive oxygen species (ROS) formation and cell cycle/stress proteins modification, including ataxia teleangectasia mutated protein (ATM), p53, p21, 8-oxoguanine DNA glycosylase (OGG1), 70 kDa heat shock protein (HSP70) and topoisomerase IIβ, as well as on DNA fragmentation, was determined. CY and CY3G treatment affect cell growth and cell proliferation, this latter in a moderately dose-dependent way. Interestingly, ROS level is decreased by any concentration of CY and, only at the lowest concentration, by CY3G. Moreover, the two molecules exert their activities increasing ATM, topoisomerase II, HSP70 and p53 expression. The analysis of DNA fragmentation by Comet assay evidences: (1) a dose-dependent increase in DNA damage only after treatment with CY3G; (2) a more evident trend in the DNA fragmentation when the treatment is performed on agarose embedded cells (cellular atypical Comet); (3) a highly dose-dependent DNA fragmentation induced by CY when the treatment is carried out on agarose embedded naked DNA (acellular atypical Comet). The present findings substantiate a possible chemotherapeutic role of anthocyanins and suggest that CY and CY3G act on CaCo2 by different mechanisms, respectively, ROS-dependent and ROS-independent.

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Ziemke, Michael, Tejas Patil, Kyle Nolan, and Stephen Malkoski. "Smad4 expression and chemosensitivity in non-small cell lung cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20550-e20550. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20550.

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e20550 Background: Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that reduced Smad4 expression was associated with increased DNA damage in both human NSCLC and murine NSCLC models and that reduced Smad4 expression inhibits DNA repair and increases sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human NSCLC as well as the relationship between Smad4 mutation and homozygous deletion and molecular alterations in other DNA repair molecules. Methods: After IRB approval, we retrospectively identified NSCLC patients who received etoposide or gemcitabine and had an evaluable tumor on CT scan at the University of Colorado Hospital between 2004 to 2014. Chemotherapeutic response was quantified by RECIST criteria, while Smad4 expression was assessed by immunohistochemistry (IHC) and quantified on a 0-300 scale. The relationship between Smad4 mutation and other DNA repair molecule alterations was assessed using TCGA data via cBioPortal. Results: Of the 21 evaluable patients, 19/21 received gemcitabine or etoposide for advanced (stage 3 or 4) disease and 10/21 received these agents with concurrent radiation therapy. Reduced Smad4 expression (IHC score < 100) occurred in 8/21 patients and was associated with non-significant trend (p = 0.18, fisher exact test) toward responsiveness to gemcitabine or etoposide. TCGA data analysis revealed that while Smad4 mutation or homozygous loss was not associated with reduced survival, Smad4 alterations were mutually exclusive to defects in DNA repair molecules. Conclusions: Reduced Smad4 expression may be a biomarker for responsiveness to treatment with chemotherapeutic drugs that inhibit DNA topoisomerase, though this study was underpowered to detect this. That Smad4 signaling alterations are mutually exclusive with alterations in other DNA repair machinery is consistent with a role of Smad4 in regulating DNA repair.

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Onono, Fredrick O., Michael A. Morgan, Jeanny Wegner, Arnold Ganser, and Christoph W. M. Reuter. "Potentiation of Topoisomerase II Inhibitor-Mediated Myeloid Leukemia Cell Kill by Farnesyltransferase Inhibitor L-744,832." Blood 110, no. 11 (November 16, 2007): 3479. http://dx.doi.org/10.1182/blood.v110.11.3479.3479.

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Abstract DNA topoisomerases (topo I and II) manage the topological state of cellular DNA during replication, transcription, recombination and chromatin remodelling by introducing temporary single- or double-strand breaks in the DNA. Several clinically important anti-tumor agents inhibit topo I (e.g. camptothecins) or topo II (e.g. anthracyclines like daunorubicin, idarubicin, and anthracenediones like mitoxantrone) religation activity, thus causing increased DNA scission which results in cell death. Anti-topo II drugs are used clinically against a wide range of tumors, including myeloid leukemias. Sensitivity to anti-topo II drugs is influenced by cell cycle, oncogenic signaling (especially RAS signaling), topo IIα levels and activity. Deregulated RAS signaling plays an important role in the molecular pathogenesis of myeloid leukemias, and strategies which target RAS signaling pathways are therapeutically promising. Inhibition of RAS post-translational modification (e.g. by farnesyltransferase inhibitors = FTIs) is one strategy to impede oncogenic RAS function in vivo. FTIs are currently being tested in clinical trials in acute myeloid leukemia (AML). It has been demonstrated that FTIs work synergistically in combination with microtubule-stabilizing drugs such as paclitaxel and inhibit MDR proteins. As many chemotherapeutics used in AML treatment target topo II (e.g. daunorubicin, etoposide, idarubicin, mitoxantrone), potential beneficial effects of FTIs in combination with topo II inhibitors were investigated in our laboratory. In order to assess the effects of FTIs alone and in combination with topo II inhibitors, several myeloid leukemia cell lines were assayed for viability, cell cycle progression, cell cycle-dependent activation of MAP kinase kinase (MEK1/2), expression of topo IIα(at the mRNA and protein levels), topo IIα activity, and induction of apoptosis. Co-treatment of several myeloid leukemia cell lines (K562, Kasumi-1, HL-60, NB-4, MV4–11, THP-1) with FTI L-744,832 and a panel of topo II inhibitors led to synergistic growth inhibition over much of the range of concentrations examined. Furthermore, pre-treatment of NB-4 cells with FTI L-744,832 led to increased induction of apoptosis by daunorubicin and idarubicin. In agreement with previous results, topo IIα expression levels in myeloid leukemia cells were higher in late S to G2/M phases of the cell cycle. In HL-60 cells, G2M arrests induced by idarubicin and daunorubicin were characterized by elevated expression levels of activated, diphosphorylated MEK-1/2 and topo IIα. While FTI L-744,832 did not significantly affect topo IIα mRNA or protein expression, HL-60 cells treated with L-744,832 alone (30μM) or in combination with idarubicin (15 μM and 5 nM, respectively) did exhibit higher levels of topo II activity as determined using a kinetoplast DNA decatenation assay. As topo IIα has been shown to be phosphorylated and activated by MAP kinase, it is interesting to speculate that activation of the MAP kinase pathway in G2/M may lead to an activation of topo IIα. Thus, the synergistic growth inhibition of myeloid leukemia cells by combining FTI L-744,832 and topo II inhibitors may be a consequence of an increased expression and/or activation of topo IIα.

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Roberge, M., J. Th'ng, J. Hamaguchi, and E. M. Bradbury. "The topoisomerase II inhibitor VM-26 induces marked changes in histone H1 kinase activity, histones H1 and H3 phosphorylation, and chromosome condensation in G2 phase and mitotic BHK cells." Journal of Cell Biology 111, no. 5 (November 1, 1990): 1753–62. http://dx.doi.org/10.1083/jcb.111.5.1753.

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We have examined the effects of topoisomerase inhibitors on the phosphorylation of histones in chromatin during the G2 and the M phases of the cell cycle. Throughout the G2 phase of BHK cells, addition of the topoisomerase II inhibitor VM-26 prevented histone H1 phosphorylation, accompanied by the inhibition of intracellular histone H1 kinase activity. However, VM-26 had no inhibitory effect on the activity of the kinase in vitro, suggesting an indirect influence on histone H1 kinase activity. Entry into mitosis was also prevented, as monitored by the absence of nuclear lamina depolymerization, chromosome condensation, and histone H3 phosphorylation. In contrast, the topoisomerase I inhibitor, camptothecin, inhibited histone H1 phosphorylation and entry into mitosis only when applied at early G2. In cells that were arrested in mitosis, VM-26 induced dephosphorylation of histones H1 and H3, DNA breaks, and partial chromosome decondensation. These changes in chromatin parameters probably reverse the process of chromosome condensation, unfolding condensed regions to permit the repair of strand breaks in the DNA that were induced by VM-26. The involvement of growth-associated histone H1 kinase in these processes raises the possibility that the cell detects breaks in the DNA through their effects on the state of DNA supercoiling in constrained domains or loops. It would appear that histone H1 kinase and topoisomerase II work coordinately in both chromosome condensation and decondensation, and that this process participates in the VM-26-induced G2 arrest of the cell.

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Hanada, Mitsuharu, Satoko Mizuno, Akihisa Fukushima, Yoshikazu Saito, Toshihiro Noguchi, and Takashi Yamaoka. "A New Antitumor Agent Amrubicin Induces Cell Growth Inhibition by Stabilizing Topoisomerase II-DNA Complex." Japanese Journal of Cancer Research 89, no. 11 (November 1998): 1229–38. http://dx.doi.org/10.1111/j.1349-7006.1998.tb00519.x.

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21

Shen, De-Qing, Ning Wu, Yan-Ping Li, Zu-Ping Wu, Hong-Bin Zhang, Zhi-Shu Huang, Lian-Quan Gu, and Lin-Kun An. "Design, Synthesis, and Cytotoxicity of Indolizinoquinoxaline-5,12-dione Derivatives, Novel DNA Topoisomerase IB Inhibitors." Australian Journal of Chemistry 63, no. 7 (2010): 1116. http://dx.doi.org/10.1071/ch09580.

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A series of new indolizinoquinoxaline-5,12-dione derivatives were designed and synthesized via a heterocyclization reaction of 6,7-dichloroquinoxaline-5,8-dione with active methylene reagents and pyridine derivatives. The synthesized compounds exhibited significant activity to inhibit the growth of four human tumour cell lines, including lung adenocarcinoma cell, large-cell lung carcinoma cell, breast carcinoma cell, and ardriamycin-resistant breast carcinoma cell at micromolar range. These compounds were also investigated for their inhibition to DNA topoisomerase IB activity. The results indicated that the indolizinoquinoxaline-5,12-dione structure might be a potential pharmacophore in anti-cancer drug design.

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22

Furuya, Kanji, and Hironori Niki. "The DNA Damage Checkpoint Regulates a Transition between Yeast and Hyphal Growth in Schizosaccharomyces japonicus." Molecular and Cellular Biology 30, no. 12 (March 5, 2010): 2909–17. http://dx.doi.org/10.1128/mcb.00049-10.

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ABSTRACT Dimorphic yeasts change between unicellular growth and filamentous growth. Many dimorphic yeasts species are pathogenic for humans and plants, being infectious as invasive hypha. We have studied the determinants of the dimorphic switch in the nonpathogenic fission yeast Schizosaccharomyces japonicus, which is evolutionarily close to the well-characterized fission yeast S. pombe. We report that camptothecin, an inhibitor of topoisomerase I, reversibly induced the unicellular to hyphal transition in S. japonicus at low concentrations of camptothecin that did not induce checkpoint arrest and the transition required the DNA checkpoint kinase Chk1. Furthermore, a mutation of chk1 induced hyphal transition without camptothecin. Thus, we identify a second function for Chk1 distinct from its role in checkpoint arrest. Activation of the switch from single cell bipolar growth to monopolar filamentous growth may assist cells to evade the source of DNA damage.

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23

Magnan, David, and David Bates. "Regulation of DNA Replication Initiation by Chromosome Structure." Journal of Bacteriology 197, no. 21 (August 17, 2015): 3370–77. http://dx.doi.org/10.1128/jb.00446-15.

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Recent advancements in fluorescence imaging have shown that the bacterial nucleoid is surprisingly dynamic in terms of both behavior (movement and organization) and structure (density and supercoiling). Links between chromosome structure and replication initiation have been made in a number of species, and it is universally accepted that favorable chromosome structure is required for initiation in all cells. However, almost nothing is known about whether cells use changes in chromosome structure as a regulatory mechanism for initiation. Such changes could occur during natural cell cycle or growth phase transitions, or they could be manufactured through genetic switches of topoisomerase and nucleoid structure genes. In this review, we explore the relationship between chromosome structure and replication initiation and highlight recent work implicating structure as a regulatory mechanism. A three-component origin activation model is proposed in which thermal and topological structural elements are balanced withtrans-acting control elements (DnaA) to allow efficient initiation control under a variety of nutritional and environmental conditions. Selective imbalances in these components allow cells to block replication in response to cell cycle impasse, override once-per-cell-cycle programming during growth phase transitions, and promote reinitiation when replication forks fail to complete.

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Neukam, Karin, Nuria Pastor, and Felipe Cortés. "Tea flavanols inhibit cell growth and DNA topoisomerase II activity and induce endoreduplication in cultured Chinese hamster cells." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 654, no. 1 (June 2008): 8–12. http://dx.doi.org/10.1016/j.mrgentox.2008.03.013.

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Lukitasari, Mifetika, Dwi Adi Nugroho, and Nashi Widodo. "Chlorogenic Acid: The Conceivable Chemosensitizer Leading to Cancer Growth Suppression." Journal of Evidence-Based Integrative Medicine 23 (January 1, 2018): 2515690X1878962. http://dx.doi.org/10.1177/2515690x18789628.

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New paradigm in cancer pathogenesis revealed that microenvironmental conditions significantly contribute to cancer. Hence, Warburg stated that cancer is a metabolic disease. Chlorogenic acid (CGA) is a polyphenol that is found abundantly in coffee. This compound has proven ability in ameliorating some metabolic diseases through various pathways. This article will elaborate the potency of CGA as a chemosensitizer in suppressing tumor growth through a metabolic pathway. AMPK pathway is the main cell metabolic pathway that is activated by CGA in some studies. Moreover, CGA inhibited EGFR/PI3K/mTOR, HIF, VEGF pathways and MAPK/ERK pathway that may suppress tumor cell growth. Furthermore, CGA induced intracellular DNA damage and topoisomerase I- and II-DNA complexes formation that plays a key role in apoptosis. Conclusively, based on the ability of CGA in activate and inhibit some important pathways in cancer metabolism, it may act as a chemosensitizing agent leading to cancer growth suppression.

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Bielawski, Krzysztof, Katarzyna Winnicka, and Anna Bielawska. "Inhibition of DNA Topoisomerases I and II, and Growth Inhibition of Breast Cancer MCF-7 Cells by Ouabain, Digoxin and Proscillaridin A." Biological & Pharmaceutical Bulletin 29, no. 7 (2006): 1493–97. http://dx.doi.org/10.1248/bpb.29.1493.

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Ishimaru, Chisato, Toshifumi Takeuchi, Fumio Sugawara, Hiromi Yoshida, and Yoshiyuki Mizushina. "Inhibitory Effects of Diacylglyceride Phospholipids on DNA Polymerase and Topoisomerase Activities, and Human Cancer Cell Growth." Medicinal Chemistry 6, no. 3 (May 1, 2010): 114–22. http://dx.doi.org/10.2174/1573406411006030114.

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28

Ishimaru, Chisato, Yuko Yonezawa, Isoko Kuriyama, Masayuki Nishida, Hiromi Yoshida, and Yoshiyuki Mizushina. "Inhibitory Effects of Cholesterol Derivatives on DNA Polymerase and Topoisomerase Activities, and Human Cancer Cell Growth." Lipids 43, no. 4 (January 24, 2008): 373–82. http://dx.doi.org/10.1007/s11745-007-3149-y.

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29

Wu, Kun-Ming, Chih-Wen Chi, Jerry Cheng-Yen Lai, Yu-Jen Chen, and Yu Ru Kou. "TLC388 Induces DNA Damage and G2 Phase Cell Cycle Arrest in Human Non-Small Cell Lung Cancer Cells." Cancer Control 27, no. 1 (January 1, 2020): 107327481989797. http://dx.doi.org/10.1177/1073274819897975.

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TLC388, a camptothecin-derivative targeting topoisomerase I, is a potential anticancer drug. In this study, its effect on A549 and H838 human non-small cell lung cancer (NSCLC) cells was investigated. Cell viability and proliferation were determined by thiazolyl blue tetrazolium bromide and clonogenic assays, respectively, and cell cycle analysis and detection of phosphorylated histone H3 (Ser10) were performed by flow cytometry. γ-H2AX protein; G2/M phase-associated molecules ataxia-telangiectasia mutated (ATM), CHK1, CHK2, CDC25C, CDC2, and cyclin B1; and apoptosis were assessed with immunofluorescence staining, immunoblotting, and an annexin V assay, respectively. The effect of co-treatment with CHIR124 (a checkpoint kinase 1 [CHK1] inhibitor) was also studied. TLC388 decreased the viability and proliferation of cells of both NSCLC lines in a dose-dependent manner. TLC388 inhibited the viability of NSCLC cell lines with an estimated concentration of 50% inhibition (IC50), which was 4.4 and 4.1 μM for A549 and H838 cells, respectively, after 24 hours. Moreover, it resulted in the accumulation of cells at the G2/M phase and increased γ-H2AX levels in A549 cells. Levels of the G2 phase–related molecules phosphorylated ATM, CHK1, CHK2, CDC25C, and cyclin B1 were increased in TLC388-treated cells. CHIR124 enhanced the cytotoxicity of TLC388 toward A549 and H838 cells and induced apoptosis of the former. TLC388 inhibits NSCLC cell growth by inflicting DNA damage and activating G2/M checkpoint proteins that trigger G2 phase cell cycle arrest to enable DNA repair. CHIR124 enhanced the cytotoxic effect of TLC388 and induced apoptosis.

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30

Sadoff, B. U., S. Heath-Pagliuso, I. B. Castaño, Y. Zhu, F. S. Kieff, and M. F. Christman. "Isolation of mutants of Saccharomyces cerevisiae requiring DNA topoisomerase I." Genetics 141, no. 2 (October 1, 1995): 465–79. http://dx.doi.org/10.1093/genetics/141.2.465.

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Abstract Despite evidence that DNA topoisomerase I is required to relieve torsional stress during DNA replication and transcription, yeast strains with a top1 null mutation are viable and display no gross defects in DNA or RNA synthesis, possibly because other proteins provide overlapping functions. We isolated mutants whose inviablility or growth defect is relieved when TOP1 is expressed [trf mutants (topoisomerase one-requiring function)]. The TRF genes define at least four complementation groups. TRF3 is allelic to TOP2. TRF1 is allelic to HPR1, previously shown to be homologous to TOP1 over two short regions. TRF4 encodes a novel 584-amino acid protein with homology to the N-terminus of Saccharomyces cerevisiae topo I. Like top1 mutants, trf4 mutants have elevated rDNA recombination and fail to shut off RNA polymerase II transcription in stationary phase. trf4 null mutants are cs for viability, display reduced expression of GAL1 and Cell Cycle Box UAS::LacZ fusions, and are inviable in combination with trfI null mutants, indicating that both proteins may share a common function with DNA topoisomerase I. The existence of multiple TRF complementation groups suggests that not all biological functions of topo I can be carried out by topo II.

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Austin, C. A., S. Patel, K. Ono, H. Nakane, and L. M. Fisher. "Site-specific DNA cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivatives." Biochemical Journal 282, no. 3 (March 15, 1992): 883–89. http://dx.doi.org/10.1042/bj2820883.

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Four naturally occurring flavones (baicalein, quercetin, quercetagetin and myricetin) and two novel catechins [(-)-epicatechin gallate and (-)-epigallocatechin gallate, from the tea plant Camellia sinensis], which are known inhibitors of reverse transcriptase, were shown to induce mammalian topoisomerase II-dependent DNA-cleavage in vitro. The flavones differed from the catechins in causing unwinding of duplex DNA, but both classes of compound induced enzymic DNA breakage at the same sites on DNA. Moreover, the cleavage specificity was the same as that for the known intercalator 4′-(acridin-9-ylamino)methanesulphon-m-anisidide, suggesting that these agents trap the same cleavable complex. Analysis of some 30 flavonoid compounds allowed elucidation of the structure-function relationships for topoisomerase II-mediated DNA cleavage. For flavonoid inhibitors an unsaturated double bond between positions 2 and 3 of the pyrone ring and hydroxy groups at the 5, 7, 3′ and 4′ positions favoured efficient cleavage. Hydroxy substitutions could be tolerated at the 3, 6 and 5′ positions. Indeed, the absence of substituents at the 3′, 4′ and 5′ positions could be compensated by a hydroxy group at position 6 (baicalein). Similar requirements have been reported for flavonoid inhibitors of protein kinase C that act competitively with ATP, suggesting interaction with a conserved protein feature. Formation of the cleavable complex is a cytotoxic lesion that may contribute to the growth-inhibitory properties of flavones observed for three human tumour cell lines. These results are discussed in regard to the selectivity of antiviral agents.

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Matias-Barrios, Victor M., Mariia Radaeva, Chia-Hao Ho, Joseph Lee, Hans Adomat, Nada Lallous, Artem Cherkasov, and Xuesen Dong. "Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy." Cancers 13, no. 15 (July 22, 2021): 3675. http://dx.doi.org/10.3390/cancers13153675.

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Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

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Fagundes, Marcia R. Z. Kress, Larissa Fernandes, Marcela Savoldi, Steven D. Harris, Maria H. S. Goldman, and Gustavo H. Goldman. "Identification of a Topoisomerase I Mutant, scsA1, as an Extragenic Suppressor of a Mutation in scaANBS1, the Apparent Homolog of Human Nibrin in Aspergillus nidulans." Genetics 164, no. 3 (July 1, 2003): 935–45. http://dx.doi.org/10.1093/genetics/164.3.935.

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Abstract The Mre11-Rad50-Nbs1 protein complex has emerged as a central player in the human cellular DNA damage response, and recent observations suggest that these proteins are at least partially responsible for the linking of DNA damage detection to DNA repair and cell cycle checkpoint functions. Mutations in scaANBS1, which encodes the apparent homolog of human nibrin in Aspergillus nidulans, inhibit growth in the presence of the antitopoisomerase I drug camptothecin. This article describes the selection and characterization of extragenic suppressors of the scaA1 mutation, with the aim of identifying other proteins that interfere with the pathway or complex in which the ScaA would normally be involved. Fifteen extragenic suppressors of the scaA1 mutation were isolated. The topoisomerase I gene can complement one of these suppressors. Synergistic interaction between the scaANBS1 and scsATOP1 genes in the presence of DNA-damaging agents was observed. Overexpression of topoisomerase I in the scaA1 mutant causes increased sensitivity to DNA-damaging agents. The scsATOP1 and the scaANBS1 gene products could functionally interact in pathways that either monitor or repair DNA double-strand breaks.

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Konkoľová, Eva, Monika Hudáčová, Slávka Hamuľaková, Rastislav Jendželovský, Jana Vargová, Juraj Ševc, Peter Fedoročko, and Mária Kožurková. "Tacrine-Coumarin Derivatives as Topoisomerase Inhibitors with Antitumor Effects on A549 Human Lung Carcinoma Cancer Cell Lines." Molecules 26, no. 4 (February 20, 2021): 1133. http://dx.doi.org/10.3390/molecules26041133.

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A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives 1a–2c) in order to test the compounds’ ability to inhibit both cancer cell growth and topoisomerase I and II activity. The ability of human topoisomerase I (hTOPI) and II to relax supercoiled plasmid DNA in the presence of various concentrations of the tacrine-coumarin hybrid molecules was studied with agarose gel electrophoresis. The biological activities of the derivatives were studied using MTT assays, clonogenic assays, cell cycle analysis and quantification of cell number and viability. The content and localization of the derivatives in the cells were analysed using flow cytometry and confocal microscopy. All of the studied compounds were found to have inhibited topoisomerase I activity completely. The effect of the tacrine-coumarin hybrid compounds on cancer cells is likely to be dependent on the length of the chain between the tacrine and coumarin moieties (1c, 1d = tacrine-(CH2)8–9-coumarin). The most active of the tested compounds, derivatives 1c and 1d, both display longer chains.

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Chakraverty, Ronjon K., Jonathan M. Kearsey, Thomas J. Oakley, Muriel Grenon, Maria-Angeles de la Torre Ruiz, Noel F. Lowndes, and Ian D. Hickson. "Topoisomerase III Acts Upstream of Rad53p in the S-Phase DNA Damage Checkpoint." Molecular and Cellular Biology 21, no. 21 (November 1, 2001): 7150–62. http://dx.doi.org/10.1128/mcb.21.21.7150-7162.2001.

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ABSTRACT Deletion of the Saccharomyces cerevisiae TOP3gene, encoding Top3p, leads to a slow-growth phenotype characterized by an accumulation of cells with a late S/G2content of DNA (S. Gangloff, J. P. McDonald, C. Bendixen, L. Arthur, and R. Rothstein, Mol. Cell. Biol. 14:8391–8398, 1994). We have investigated the function of TOP3 during cell cycle progression and the molecular basis for the cell cycle delay seen in top3Δ strains. We show that top3Δ mutants exhibit a RAD24-dependent delay in the G2 phase, suggesting a possible role for Top3p in the resolution of abnormal DNA structures or DNA damage arising during S phase. Consistent with this notion,top3Δ strains are sensitive to killing by a variety of DNA-damaging agents, including UV light and the alkylating agent methyl methanesulfonate, and are partially defective in the intra-S-phase checkpoint that slows the rate of S-phase progression following exposure to DNA-damaging agents. This S-phase checkpoint defect is associated with a defect in phosphorylation of Rad53p, indicating that, in the absence of Top3p, the efficiency of sensing the existence of DNA damage or signaling to the Rad53 kinase is impaired. Consistent with a role for Top3p specifically during S phase, top3Δ mutants are sensitive to the replication inhibitor hydroxyurea, expression of the TOP3 mRNA is activated in late G1 phase, and DNA damage checkpoints operating outside of S phase are unaffected by deletion of TOP3. All of these phenotypic consequences of loss of Top3p function are at least partially suppressed by deletion of SGS1, the yeast homologue of the human Bloom's and Werner's syndrome genes. These data implicate Top3p and, by inference, Sgs1p in an S-phase-specific role in the cellular response to DNA damage. A model proposing a role for these proteins in S phase is presented.

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Mo, Xiao-mei, Zhan-fang Chen, Xin Qi, Yan-tuan Li, and Jing Li. "DNA-Binding and Topoisomerase-I-Suppressing Activities of Novel Vanadium Compound Van-7." Bioinorganic Chemistry and Applications 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/756374.

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Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal anticancer agents in combination to its low toxicity. Here, we found a vanadium compound Van-7 as an inhibitor of Topo I other than Topo II using topoisomerase-mediated supercoiled DNA relaxation assay. Agarose gel electrophoresis and comet assay showed that Van-7 treatment did not produce cleavable complexes like HCPT, thereby suggesting that Topo I inhibition occurred upstream of the relegation step. Further studies revealed that Van-7 inhibited Topo I DNA binding involved in its intercalating DNA. Van-7 did not affect the catalytic activity of DNase I even up to100 μM. Van-7 significantly suppressed the growth of cancer cell lines with IC50at nanomolar concentrations and arrested cell cycle of A549 cells at G2/M phase. All these results indicate that Van-7 is a potential selective Topo I inhibitor with anticancer activities as a kind of Topo I suppressor, not Topo I poison.

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Song, Mengqiu, Shuying Yin, Ran Zhao, Kangdong Liu, Joydeb Kumar Kundu, Jung-Hyun Shim, Mee-Hyun Lee, and Zigang Dong. "(S)-10-Hydroxycamptothecin Inhibits Esophageal Squamous Cell Carcinoma Growth In Vitro and In Vivo Via Decreasing Topoisomerase I Enzyme Activity." Cancers 11, no. 12 (December 6, 2019): 1964. http://dx.doi.org/10.3390/cancers11121964.

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Topoisomerase (TOP) I plays a major role in the process of supercoiled DNA relaxation, thereby facilitating DNA replication and cell cycle progression. The expression and enzymatic activity of TOP I is positively correlated with tumor progression. Although the anticancer activity of (S)-10-Hydroxycamptothecin (HCPT), a TOP I specific inhibitor, has been reported in various cancers, the effect of HCPT on esophageal cancer is yet to be examined. In this study, we investigate the potential of HCPT to inhibit the growth of ESCC cells in vitro and verify its anti-tumor activity in vivo by using a patient-derived xenograft (PDX) tumor model in mice. Our study revealed the overexpression of TOP I in ESCC cells and treatment with HCPT inhibited TOP I enzymatic activity at 24 h and decreased expression at 48 h and 72 h. HCPT also induced DNA damage by increasing the expression of H2A.XS139. HCPT significantly decreased the proliferation and anchorage-independent growth of ESCC cells (KYSE410, KYSE510, KYSE30, and KYSE450). Mechanistically, HCPT inhibited the G2/M phase cell cycle transition, decreased the expression of cyclin B1, and elevated p21 expression. In addition, HCPT stimulated ESCC cells apoptosis, which was associated with elevated expression of cleaved PARP, cleaved caspase-3, cleaved caspase-7, Bax, Bim, and inhibition of Bcl-2 expression. HCPT dramatically suppressed PDX tumor growth and decreased the expression of Ki-67 and TOP I and increased the level of cleaved caspase-3 and H2A.XS139 expression. Taken together, our data suggested that HCPT inhibited ESCC growth, arrested cell cycle progression, and induced apoptosis both in vitro and in vivo via decreasing the expression and activity of TOP I enzyme.

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38

Willmore, Elaine, Sarah de Caux, Nicola J. Sunter, Michael J. Tilby, Graham H. Jackson, Caroline A. Austin, and Barbara W. Durkacz. "A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia." Blood 103, no. 12 (June 15, 2004): 4659–65. http://dx.doi.org/10.1182/blood-2003-07-2527.

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Abstract We report for the first time the use of a selective small-molecule inhibitor of DNA repair to potentiate topoisomerase II (topo II) poisons, identifying DNA-dependent protein kinase (DNA-PK) as a potential target for leukemia therapy. Topo II poisons form cleavable complexes that are processed to DNA double-strand breaks (DSBs). DNA-PK mediates nonhomologous end joining (NHEJ). Inhibition of this DSB repair pathway may sensitize cells to topo II poisons. We investigated the effects of a novel DNA-PK inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), on the response to topo II poisons using K562 leukemia cells. NU7026 (10 μM) potentiated the growth inhibition of idarubicin, daunorubicin, doxorubicin, etoposide, amsacrine (mAMSA), and mitroxantrone with potentiation factors at 50% growth inhibition ranging from approximately 19 for mAMSA to approximately 2 for idarubicin (potentiation of etoposide was confirmed by clonogenic assay). In contrast, NU7026 did not potentiate camptothecin or cytosine arabinoside (araC). NU7026 did not affect the levels of etoposide-induced topo IIα or β cleavable complexes. NU7026 alone had no effect on cell cycle distribution, but etoposide-induced accumulation in G2/M was increased by NU7026. A concentration-dependent increase in etoposide-induced DSB levels was increased by NU7026. The mechanism of NU7026 potentiation of topo II poisons involves inhibition of NHEJ and a G2/M checkpoint arrest. (Blood. 2004;103:4659-4665)

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Sternglanz, R. "DNA topoisomerases." Current Opinion in Cell Biology 1, no. 3 (June 1989): 533–35. http://dx.doi.org/10.1016/0955-0674(89)90016-1.

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Hsieh, T. "DNA topoisomerases." Current Opinion in Cell Biology 2, no. 3 (June 1990): 461–63. http://dx.doi.org/10.1016/0955-0674(90)90128-2.

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Hsieh, Tao-shih. "DNA topoisomerases." Current Opinion in Cell Biology 4, no. 3 (June 1992): 396–400. http://dx.doi.org/10.1016/0955-0674(92)90004-v.

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Uckun, FM, CF Stewart, G. Reaman, LM Chelstrom, J. Jin, M. Chandan-Langlie, KG Waddick, J. White, and WE Evans. "In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells." Blood 85, no. 10 (May 15, 1995): 2817–28. http://dx.doi.org/10.1182/blood.v85.10.2817.bloodjournal85102817.

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Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.

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Shapiro, Paul S., Anne M. Whalen, Nicholas S. Tolwinski, Julie Wilsbacher, Stacie J. Froelich-Ammon, Marileila Garcia, Neil Osheroff, and Natalie G. Ahn. "Extracellular Signal-Regulated Kinase Activates Topoisomerase IIα through a Mechanism Independent of Phosphorylation." Molecular and Cellular Biology 19, no. 5 (May 1, 1999): 3551–60. http://dx.doi.org/10.1128/mcb.19.5.3551.

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ABSTRACT The mitogen-activated protein (MAP) kinases, extracellular signal-related kinase 1 (ERK1) and ERK2, regulate cellular responses by mediating extracellular growth signals toward cytoplasmic and nuclear targets. A potential target for ERK is topoisomerase IIα, which becomes highly phosphorylated during mitosis and is required for several aspects of nucleic acid metabolism, including chromosome condensation and daughter chromosome separation. In this study, we demonstrated interactions between ERK2 and topoisomerase IIα proteins by coimmunoprecipitation from mixtures of purified enzymes and from nuclear extracts. In vitro, diphosphorylated active ERK2 phosphorylated topoisomerase IIα and enhanced its specific activity by sevenfold, as measured by DNA relaxation assays, whereas unphosphorylated ERK2 had no effect. However, activation of topoisomerase II was also observed with diphosphorylated inactive mutant ERK2, suggesting a mechanism of activation that depends on the phosphorylation state of ERK2 but not on its kinase activity. Nevertheless, activation of ERK by transient transfection of constitutively active mutant MAP kinase kinase 1 (MKK1) enhanced endogenous topoisomerase II activity by fourfold. Our findings indicate that ERK regulates topoisomerase IIα in vitro and in vivo, suggesting a potential target for the MKK/ERK pathway in the modulation of chromatin reorganization events during mitosis and in other phases of the cell cycle.

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MATSUI, YUKI, TOSHIFUMI TAKEUCHI, YUKO KUMAMOTO-YONEZAWA, MASAHARU TAKEMURA, FUMIO SUGAWARA, HIROMI YOSHIDA, and YOSHIYUKI MIZUSHINA. "The relationship between the molecular structure of natural acetogenins and their inhibitory activities which affect DNA polymerase, DNA topoisomerase and human cancer cell growth." Experimental and Therapeutic Medicine 1, no. 1 (2010): 19–26. http://dx.doi.org/10.3892/etm_00000004.

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Yonezawa, Yuko, Isoko Kuriyama, Atsushi Fukuoh, Tsuyoshi Muta, Dongchon Kang, Masaharu Takemura, Ikuo Kato, Hiromi Yoshida, and Yoshiyuki Mizushina. "Inhibitory effect of coenzyme Q1 on eukaryotic DNA polymerase gamma and DNA topoisomerase II activities on the growth of a human cancer cell line." Cancer Science 97, no. 8 (August 2006): 716–23. http://dx.doi.org/10.1111/j.1349-7006.2006.00236.x.

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Wasil, Laura R., Leizhen Wei, Christopher Chang, Li Lan, and Kathy H. Y. Shair. "Regulation of DNA Damage Signaling and Cell Death Responses by Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) and LMP2A in Nasopharyngeal Carcinoma Cells." Journal of Virology 89, no. 15 (May 13, 2015): 7612–24. http://dx.doi.org/10.1128/jvi.00958-15.

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ABSTRACTNasopharyngeal carcinoma (NPC) is closely associated with latent Epstein-Barr virus (EBV) infection. Although EBV infection of preneoplastic epithelial cells is not immortalizing, EBV can modulate oncogenic and cell death mechanisms. The viral latent membrane proteins 1 (LMP1) and LMP2A are consistently expressed in NPC and can cooperate in bitransgenic mice expressed from the keratin-14 promoter to enhance carcinoma development in an epithelial chemical carcinogenesis model. In this study, LMP1 and LMP2A were coexpressed in the EBV-negative NPC cell line HK1 and examined for combined effects in response to genotoxic treatments. In response to DNA damage activation, LMP1 and LMP2A coexpression reduced γH2AX (S139) phosphorylation and caspase cleavage induced by a lower dose (5 μM) of the topoisomerase II inhibitor etoposide. Regulation of γH2AX occurred before the onset of caspase activation without modulation of other DNA damage signaling mediators, including ATM, Chk1, or Chk2, and additionally was suppressed by inducers of DNA single-strand breaks (SSBs) and replication stress. Despite reduced DNA damage repair signaling, LMP1-2A coexpressing cells recovered from cytotoxic doses of etoposide; however, LMP1 expression was sufficient for this effect. LMP1 and LMP2A coexpression did not enhance cell growth, with a moderate increase of cell motility to fibronectin. This study supports that LMP1 and LMP2A jointly regulate DNA repair signaling and cell death activation with no further enhancement in the growth properties of neoplastic cells.IMPORTANCENPC is characterized by clonal EBV infection and accounts for >78,000 annual cancer cases with increased incidence in regions where EBV is endemic, such as southeast Asia. The latent proteins LMP1 and LMP2A coexpressed in NPC can individually enhance growth or survival properties in epithelial cells, but their combined effects and potential regulation of DNA repair and checkpoint mechanisms are relatively undetermined. In this study, LMP1-2A coexpression suppressed activation of the DNA damage response (DDR) protein γH2AX induced by selective genotoxins that promote DNA replication stress or SSBs. Expression of LMP1 was sufficient to recover cells, resulting in outgrowth of LMP1 and LMP1-2A-coexpressing cells and indicating distinct LMP1-dependent effects in the restoration of replicative potential. These findings demonstrate novel properties for LMP1 and LMP2A in the cooperative modulation of DDR and apoptotic signaling pathways, further implicating both proteins in the progression of NPC and epithelial malignancies.

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Fan, Saijun, Yong Xian Ma, Min Gao, Ren-Qi Yuan, Qinghui Meng, Itzhak D. Goldberg, and Eliot M. Rosen. "The Multisubstrate Adapter Gab1 Regulates Hepatocyte Growth Factor (Scatter Factor)–c-Met Signaling for Cell Survival and DNA Repair." Molecular and Cellular Biology 21, no. 15 (August 1, 2001): 4968–84. http://dx.doi.org/10.1128/mcb.21.15.4968-4984.2001.

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ABSTRACT Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIα inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.

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MARQUIS, J. F., M. DROLET, and M. OLIVIER. "Consequence of Hoechst 33342-mediated Leishmania DNA topoisomerase-I inhibition on parasite replication." Parasitology 126, no. 1 (January 2003): 21–30. http://dx.doi.org/10.1017/s0031182002002524.

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This study reports that inhibition of Leishmania Topo-I with the minor groove-binding ligands (MGBLs) Hoechst 33342 (Ho342) blocks parasite growth in culture by mechanisms involving DNA breakage. While Ho342 inhibited the replication of several species of Leishmania in a dose- and time-dependent manner, Ho258 was not effective. Cytofluorometric analysis suggested that superior effectiveness of Ho342 over Ho258 was attributed to Leishmania parasites being more permeable toward Ho342. This observation was supported by the ability of both Ho342 and Ho258 to block the relaxation of supercoiled pBR322 DNA by Leishmania Topo-I. The Ho342 specificity toward L. donovani Topo-I was reinforced by the observation that increased Topo-I gene expression and Topo-I activity in Leishmania was paralleled by augmented resistance for this compound. Furthermore, the capacity of NaCl treatment to reverse MGBL-mediated DNA break suggests that Ho342 targetted Topo-I. Moreover, we observed that Ho342-inducible arrest of Leishmania growth was accompanied by G1 arrest and induction of cell death that closely resembles apoptosis. Taken together, our results suggest that MGBL compounds show promise as Topo-I inhibitors against Leishmania infection.

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Roychoudhury, Siddhartha, Kelly M. Makin, Tracy L. Twinem, David T. Stanton, Sandra L. Nelson, and Carl E. Catrenich. "Development and Use of a High-Throughput Bacterial DNA Gyrase Assay to Identify Mammalian Topoisomerase II Inhibitors with Whole-Cell Anticancer Activity." Journal of Biomolecular Screening 8, no. 2 (April 2003): 157–63. http://dx.doi.org/10.1177/1087057103252302.

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A high-throughput screen (HTS)was developed and used to identify inhibitors of bacterial DNA gyrase. Among the validated hits were 53 compounds that also inhibited mammalian topoisomerase II with IC50 values of <12.5 µg/mL for 51 of them. Using computational methods, these compounds were subjected to cluster analysis to categorize them according to their chemical and structural properties. Nine compounds from different clusters were tested for their whole-cell inhibitory activity against 3 cancer cell lines—NCI-H460 (lung), MCF7 (breast), and SF-268 (CNS)—at a concentration of 100 µM. Five compounds inhibited cell growth by >50% for all 3 cell lines tested. These compounds were tested further against a panel of 53 to 57 cell lines representing leukemia, melanoma, colon, CNS, ovarian, renal, prostate, breast, and non–small cell lung cancers. In this assay, PGE-7143417 was found to be the most potent compound, which inhibited the growth of all the cell lines by 50% at a concentration range of 0.31 to 2.58 µM, with an average of 1.21 µM. An additional 17 compounds were also tested separately against a panel of 10 cell lines representing melanoma, colon, lung, mammary, ovarian, prostate, and renal cancers. In this assay, 4 compounds—PGE-3782569, PGE-7411516, PGE-2908955, and PGE-3521917—were found to have activity with concentrations for 50% cell growth inhibition in the 0.59 to 3.33, 22.5 to 59.1, 7.1 to >100, and 24.7 to >100 µM range. ( Journal of Biomolecular Screening 2003:157-163)

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Poljaková, Jitka, Tomáš Eckschlager, Jana Hřebačková, Jan Hraběta, and Marie Stiborová. "The comparison of cytotoxicity of the anticancer drugs doxorubicin and ellipticine to human neuroblastoma cells." Interdisciplinary Toxicology 1, no. 2 (September 1, 2008): 186–89. http://dx.doi.org/10.2478/v10102-010-0036-9.

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The comparison of cytotoxicity of the anticancer drugs doxorubicin and ellipticine to human neuroblastoma cellsEllipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the cytotoxicity of ellipticine to human neuroblastoma derived cell lines IMR-32 and UKF-NB-4 was investigated. Treatment of neuroblastoma cells with ellipticine was compared with that of these cancer cells with doxorubicin. The toxicity of ellipticine was essentially the same as that of doxorubicin to UKF-NB-4 cells, but doxorubicin is much more effective to inhibit the growth of the IMR-32 cell line than ellipticine. Hypoxic conditions used for the cell cultivation resulted in a decrease in ellipticine and/or doxorubicin toxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.

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Journal articles on the topic 'DNA topoisomerases; Cell growth'

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