Anthocyanidins Modulate the Activity of Human DNA Topoisomerases I and II and Affect Cellular DNA Integrity

2005 ◽  
Vol 18 (9) ◽  
pp. 1395-1404 ◽  
Author(s):  
Michael Habermeyer ◽  
Jessica Fritz ◽  
Hans U. Barthelmes ◽  
Morten O. Christensen ◽  
Morten K. Larsen ◽  
...  
Keyword(s):  
Dna Integrity ◽  
Dna Topoisomerases ◽  
Human Dna ◽  
Cellular Dna

Antitumor Effect of Pomolic Acid in Acute Myeloid Leukemia Cells Involves Cell Death, Decreased Cell Growth and Topoisomerases Inhibition

2019 ◽  
Vol 18 (10) ◽  
pp. 1457-1468
Author(s):  
Michelle X.G. Pereira ◽  
Amanda S.O. Hammes ◽  
Flavia C. Vasconcelos ◽  
Aline R. Pozzo ◽  
Thaís H. Pereira ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Natural Compound ◽  
Dna Topoisomerases ◽  
Human Dna ◽  
Pomolic Acid ◽  
Acute Myeloid

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.

Oncogenes in Laryngeal Cancer: Serial Passage of Transformed Cellular DNA

1985 ◽  
Vol 93 (3) ◽  
pp. 346-350 ◽  
Author(s):  
William H. Friedman ◽  
Barry N. Rosenblum ◽  
Paul Loewenstein ◽  
Helen Thornton ◽  
George Katsantonis ◽  
...  
Keyword(s):  
Laryngeal Cancer ◽  
Dna Sequences ◽  
Squamous Cell Cancer ◽  
Cell Cancer ◽  
Serial Passage ◽  
3T3 Cells ◽  
Human Dna ◽  
Cellular Dna ◽  
Nih 3T3 ◽  
Narrow Bands

DNA originally extracted from squamous cell cancer of the larynx has been serially passaged through transformed populations of NIH/3T3 mouse fibroblasts. The transformed foci were then harvested, cloned to volume, and incubated with a fresh population of NIH/3T3 cells in a second passage. Transforming efficiencies were enhanced by serial passage. In addition, Southern Blot analysis of the transformed foci revealed hybridization between transformant DNA and human probe DNA from the Alu family of conserved human DNA sequences. In the first passage this hybridization took the form of diffuse homology throughout the entire molecular weight distribution. The second-passage DNA showed “narrow bands” indicating the possibility that an oncogene has been identified in laryngeal cancer and that serial passage has eliminated contaminating human sequences. Repetitive transfection in third- and fourth-passage studies is now being completed.

The Topopyrones Poison Human DNA Topoisomerases I and II

2008 ◽  
Vol 130 (39) ◽  
pp. 12888-12889 ◽  
Author(s):  
Qasim A. Khan ◽  
Mark A. Elban ◽  
Sidney M. Hecht
Keyword(s):  
Dna Topoisomerases ◽  
Human Dna

Human DNA topoisomerases IIα and IIβ can functionally substitute for yeast TOP2 in chromosome segregation and recombination

1996 ◽  
Vol 252 (1-2) ◽  
pp. 79-86 ◽  
Author(s):  
Sanne Jensen ◽  
Charles S. Redwood ◽  
John R. Jenkins ◽  
Anni H. Andersen ◽  
Ian D. Hickson
Keyword(s):  
Chromosome Segregation ◽  
Dna Topoisomerases ◽  
Human Dna

DNA Binding by Fagaronine and Ethoxidine, Inhibitors of Human DNA Topoisomerases I and II, Probed by SERS and Flow Linear Dichroism Spectroscopy†

1999 ◽  
Vol 103 (11) ◽  
pp. 2008-2013 ◽  
Author(s):  
Anatoli Ianoul ◽  
Fabrice Fleury ◽  
Olivier Duval ◽  
Roger Waigh ◽  
Jean-Claude Jardillier ◽  
...  
Keyword(s):  
Dna Binding ◽  
Linear Dichroism ◽  
Dna Topoisomerases ◽  
Human Dna

New spiro-acridines: DNA interaction, antiproliferative activity and inhibition of human DNA topoisomerases

2016 ◽  
Vol 92 ◽  
pp. 467-475 ◽  
Author(s):  
Sinara Mônica Vitalino de Almeida ◽  
Elizabeth Almeida Lafayette ◽  
Willams Leal Silva ◽  
Vanessa de Lima Serafim ◽  
Thais Meira Menezes ◽  
...  
Keyword(s):  
Antiproliferative Activity ◽  
Dna Interaction ◽  
Dna Topoisomerases ◽  
Human Dna

scholarly journals Rational Design of Human DNA Ligase Inhibitors that Target Cellular DNA Replication and Repair

2008 ◽  
Vol 68 (9) ◽  
pp. 3169-3177 ◽  
Author(s):  
Xi Chen ◽  
Shijun Zhong ◽  
Xiao Zhu ◽  
Barbara Dziegielewska ◽  
Tom Ellenberger ◽  
...  
Keyword(s):  
Dna Replication ◽  
Rational Design ◽  
Dna Ligase ◽  
Human Dna ◽  
Dna Replication And Repair ◽  
Cellular Dna

scholarly journals A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice: Impact of Sex and Age

2020 ◽  
Vol 21 (18) ◽  
pp. 6600
Author(s):  
Nicola Winkelbeiner ◽  
Viktoria K. Wandt ◽  
Franziska Ebert ◽  
Kristina Lossow ◽  
Ezgi E. Bankoglu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Decisive Role ◽  
Dna Lesions ◽  
Dna Integrity ◽  
Repair Mechanisms ◽  
Murine Liver ◽  
Base Excision ◽  
Cellular Dna

Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2’-deoxyguanosine (8-oxodG), 5-hydroxy-2’-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.

scholarly journals Novel triterpenoids inhibit both DNA polymerase and DNA topoisomerase

2000 ◽  
Vol 350 (3) ◽  
pp. 757-763 ◽  
Author(s):  
Yoshiyuki MIZUSHINA ◽  
Akira IIDA ◽  
Keisuke OHTA ◽  
Fumio SUGAWARA ◽  
Kengo SAKAGUCHI
Keyword(s):  
Ursolic Acid ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Three Dimensional ◽  
Amino Acid Sequences ◽  
Dna Topoisomerases ◽  
Deoxyribonuclease I ◽  
Human Dna ◽  
Dna Binding Sites ◽  
Human Telomerase

As described previously, we found that new triterpenoid compounds, designated fomitellic acids A and B, which selectively inhibit the activities of mammalian DNA polymerases α and β [Mizushina, Tanaka, Kitamura, Tamai, Ikeda, Takemura, Sugawara, Arai, Matsukage, Yoshida and Sakaguchi (1998) Biochem. J. 330, 1325–1332; Tanaka, Kitamura, Mizushina, Sugawara and Sakaguchi (1998) J. Nat. Prod. 61, 193–197] and that a known triterpenoid, ursolic acid, is an inhibitor of human DNA topoisomerases I and II (A. Iida, Y. Mizushina and K. Sakaguchi, unpublished work). Here we report that all of these triterpenoids are potent inhibitors of calf DNA polymerase α, rat DNA polymerase β and human DNA topoisomerases I and II, and show moderate inhibitory effects on plant DNA polymerase II and human immunodeficiency virus reverse transcriptase. However, these compounds did not influence the activities of prokaryotic DNA polymerases such as Escherichia coli DNA polymerase I or other DNA metabolic enzymes such as human telomerase, T7 RNA polymerase and bovine deoxyribonuclease I. These triterpenoids were not only mammalian DNA polymerase inhibitors but also inhibitors of DNA topoisomerases I and II even though the enzymic characteristics of DNA polymerases and DNA topoisomerases, including their modes of action, amino acid sequences and three-dimensional structures, differed markedly. These triterpenoids did not bind to DNA, suggesting that they act directly on these enzymes. Because the three-dimensional structures of fomitellic acids were shown by computer simulation to be very similar to that of ursolic acid, the DNA-binding sites of both enzymes, which compete for the inhibitors, might be very similar. Fomitellic acid A and ursolic acid prevented the growth of NUGC cancer cells, with LD50 values of 38 and 30µM respectively.

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