scholarly journals Cytotoxicity and inhibitory properties against topoisomerase II of doxorubicin and its formamidine derivatives.

2009 ◽  
Vol 56 (1) ◽  
Author(s):  
Krzysztof Kik ◽  
Kazimierz Studzian ◽  
Małgorzata Wasowska-Łukawska ◽  
Irena Oszczapowicz ◽  
Leszek Szmigiero
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Colorimetric Assay ◽  
Cellular Level ◽  
Cytotoxic Action ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Free System ◽  
Cell Free System ◽  
Pbr322 Dna

This work was undertaken to compare cytotoxicity, DNA damaging properties and effect on DNA cleavage by topoisomerase II of the anthracycline drug doxorubicin (DOX) and its two derivatives with a formamidino group containing a cyclic amine moiety such as morpholine (DOXM) or hexamethyleneimine (DOXH). The tetrazolium dye colorimetric assay was used to determine the cytotoxic activity of anthracyclines toward L1210 leukemia cells. DNA damage was measured by alkaline elution technique. The effect of anthracyclines on DNA cleavage was studied in a cell-free system containing supercoiled pBR322 DNA and purified human topoisomerase II. The cytotoxicity data and the results of studies on the mechanism of DNA break formation by anthracyclines at the cellular level and in the cell-free system showed that the presence of the formamidino group in the doxorubicin molecule reduced its ability to stimulate DNA cleavage by DNA topoisomerase II. DNA topoisomerase II is not a primary cellular target for DOXM or DOXH. An advantageous feature of formamidinoanthracyclines is their mechanism of cytotoxic action which is not related to the inhibition of DNA topoisomerase II. Therefore this class of anthracyclines seems to be a good source for selection of an anticancer drug directed toward cancer cells with the developed multidrug resistance attributed to the presence of altered DNA topoisomerase II.

Altered catalytic activity of and DNA cleavage by DNA topoisomerase II from human leukemic cells selected for resistance to VM-26

Biochemistry ◽  
1988 ◽  
Vol 27 (24) ◽  
pp. 8861-8869 ◽  
Author(s):  
Mary K. Danks ◽  
Carla A. Schmidt ◽  
Margaret C. Cirtain ◽  
D. Parker Suttle ◽  
William T. Beck
Keyword(s):  
Catalytic Activity ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Leukemic Cells ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Leukemic Cells

Glycosylated flavones as selective inhibitors of topoisomerase IV.

1997 ◽  
Vol 41 (5) ◽  
pp. 992-998 ◽  
Author(s):  
F X Bernard ◽  
S Sablé ◽  
B Cameron ◽  
J Provost ◽  
J F Desnottes ◽  
...  
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Coli Strain ◽  
Selective Inhibitors ◽  
Topoisomerase Iv ◽  
Gene Encoding ◽  
Cottonseed Flour ◽  
Dna Topoisomerase ◽  
E Coli ◽  
Pbr322 Dna

Three flavonoids which promoted Escherichia coli topoisomerase IV-dependent DNA cleavage were isolated from cottonseed flour and identified as quercetin 3-O-beta-D-glucose-[1,6]-O-alpha-L-rhamnose (rutin), quercetin 3-O-beta-D-galactose-[1,6]-O-alpha-L-rhamnose, and quercetin 3-O-beta-D-glucose (isoquercitrin). The most active one (rutin) also inhibited topoisomerase IV-dependent decatenation activity (50% inhibitory concentration, 64 microg/ml) and induced the SOS response of a permeable E. coli strain. Derivatives of quercetin glycosylated at position C-3 were shown to induce two site-specific DNA cleavages of pBR322 DNA, which were mapped by DNA sequence analysis to the gene encoding resistance to tetracycline. Cleavage at these sites was hardly detectable in cleavage reactions with quercetin or fluoroquinolones. None of the three flavonoids isolated from cottonseeds had any stimulatory activity on E. coli DNA gyrase-dependent or calf thymus topoisomerase II-dependent DNA cleavage, and they were therefore specific to topoisomerase IV. These results show that selective inhibitors of topoisomerase IV can be derived from the flavone structure. This is the first report on a DNA topoisomerase inhibitor specific for topoisomerase IV.

scholarly journals Coupling between ATP Binding and DNA Cleavage by DNA Topoisomerase II

2008 ◽  
Vol 283 (25) ◽  
pp. 17463-17476 ◽  
Author(s):  
Felix Mueller-Planitz ◽  
Daniel Herschlag
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Atp Binding ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase

Amsacrine-promoted DNA cleavage site determinants for the two human DNA topoisomerase II isoforms α and β

1996 ◽  
Vol 52 (11) ◽  
pp. 1675-1685 ◽  
Author(s):  
Katherine L. Marsh ◽  
Elaine Willmore ◽  
Stella Tinelli ◽  
Mariagrazia Cornarotti ◽  
Emma L. Meczes ◽  
...  
Keyword(s):  
Dna Cleavage ◽  
Cleavage Site ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Dna

Reduced DNA topoisomerase II activity and drug-stimulated DNA cleavage in 9-hydroxyellipticine resistant cells

1988 ◽  
Vol 37 (11) ◽  
pp. 2145-2149 ◽  
Author(s):  
Jean-Yves Charcosset ◽  
Jean-Marie Saucier ◽  
Alain Jacquemin-Sablon
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Resistant Cells

Insight into Mechanism of Action of Anticancer Benzazoles

2020 ◽  
Vol 20 (23) ◽  
pp. 2056-2069
Author(s):  
Ozum Ozturk ◽  
Esin Aki-Yalcin ◽  
Ismail Yalcin ◽  
Renate Grifitth
Keyword(s):  
Active Sites ◽  
Topoisomerase Ii ◽  
Antitumor Agents ◽  
Enzyme Inhibitors ◽  
Docking Studies ◽  
Binding Modes ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Free System ◽  
Topoisomerase Poisons

Background: Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription, and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome. This ultimately leads to the accumulation of DNA strand breaks and cell death. Methods: Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell-free system. Their interactions with the enzyme were studied by carrying out molecular docking studies using and comparing two different docking programs. Results: The results of the docking studies clarified binding modes of these compounds to the topoisomerase II enzyme. Conclusion: This study also provides guidelines to design novel and more potent antitumor agents functioning as human topoisomerase II enzyme inhibitors.

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