Catalytic topoisomerase II inhibitors in cancer therapy

Larsen, Annette K.; Escargueil, Alexandre E.; Składanowski, Andrzej

doi:10.1016/s0163-7258(03)00058-5

Cited by 352 publications

(331 citation statements)

References 80 publications

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“…These agents shifting the equilibrium of the cleavage/religation reaction can provoke permanent DNA double strand breaks (DSBs) triggering cell death and/or causing chromosomal aberrations. 9,10 Hence the need to search for new anticancer drugs able to poison TOPOII in proliferating cells and showing a moderate cytotoxic potential in quiescent ones.Recently, we have shown that RSV treatment is able to induce a delay in S progression with a concomitant increase in cH2AX expression in U87 glioma cells. 11 Furthermore, in an in vitro assay, RSV was shown to inhibit the ability of recombinant human TOPOIIa to decatenate kDNA.…”

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confidence: 99%

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Resveratrol acts as a topoisomerase II poison in human glioma cells

Leone

Basso

Polticelli

et al. 2012

Intl Journal of Cancer

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Recently, we demonstrated that Resveratrol (RSV), a well known natural stilbene, is able to induce a delay in S progression with a concomitant increase in cH2AX expression in U87 glioma cells. Furthermore, we showed that it inhibits the ability of recombinant human topoisomerase IIa to decatenate kDNA in vitro. Because proliferating tumor cells express topoisomerases at high levels and these enzymes are important targets of some of the most successful anticancer drugs, we tested whether RSV is able to poison topoisomerase IIa in glioma cells. Then, we monitored the increase of micronuclei in RSV treated U87 cells as a consequence of the conversion of TOPOII/DNA cleavable complexes to permanent DNA damage. Finally, we assayed the ability of RSV in modulating the expression of target proteins involved in DNA damage signalling, namely ATR, ATM, Chk1, Chk2 and cH2AX. Through a molecular modelling here we show that RSV binds at the TOPOII/DNA interface thus establishing several hydrogen bonds. Moreover, we show that RSV poisons TOPOIIa so inducing DNA damage; ATM, Chk2 and cH2AX are involved in the DNA damage signalling after RSV treatment.Resveratrol (3,4 0 ,5-trihydroxylstilbene), a polyphenol synthesized by a wide variety of plant species, is well known for its antitumor potential as demonstrated by many in vitro studies. 1 Nevertheless, the molecular targets of Resveratrol (RSV) activity seem not yet completely understood due to the multiplicity of RSV treatment effects in normal and transformed cultured cells. However, it is well known that RSV can disturb the normal progress of the cell cycle so decreasing the proliferation and can also induce apoptosis in cell type-and concentration-dependent mode. 2 On the other hand RSV, such as many other natural polyphenols, acts as antioxidant or prooxidant due to the intracellular presence of transition metal ions. The prooxidant activity could be an important action mechanism for its anticancer properties. 3 It has been suggested that some of the cellular effects of polyphenols, such as anti-proliferative and proapoptotic actions, could be correlated with their ability to act on topoisomerases. 4,5 These are ubiquitous nuclear enzymes that modulate the topological state of DNA by breaking and resealing one or both strands of a DNA duplex. In eukaryotic cells, type II topoisomerases, isoforms a and b, function during major cellular processes involving DNA (recombination, replication, proper chromosome structure and segregation) generating intermediate cleavable or covalent complexes with a short half-life. 6 Highly proliferating tumor cells express these enzymes, particularly Type IIa, at levels many times higher than quiescent cells 7,8 so that topoisomerases II are important targets for some of the anticancer drugs most successfully used in the treatment of human malignancies. TOPOII-targeted agents interfere with the binding between DNA and TOPOII or act by increasing the concentration of topoisomerase-DNA covalent complexes. These agents shifting the equilibrium of t...

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Resveratrol acts as a topoisomerase II poison in human glioma cells

Leone

Basso

Polticelli

et al. 2012

Intl Journal of Cancer

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“…Due to inhibiting topoisomerases activity, DNA synthesis in cells is limited and consequently cell division is reduced. Substances targeting topoisomerases fall into two categories -topoisomerase poisons and topoisomerase catalytic inhibitors 12 . The term ''topoisomerase poisons'' reflects the fact that these compounds convert this enzyme into a cell poison, which causes a range of irreversible damage to genetic material 13 .…”

Section: Introductionmentioning

confidence: 99%

Search for human DNA topoisomerase II poisons in the group of 2,5-disubstituted-1,3,4-thiadiazoles

Plech

Kaproń

Paneth

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of six 2,5-disubstituted 1,3,4-thiadiazole derivatives was synthesized and examined for cytotoxic activity in MCF-7 and MDA-MB-231 breast cancer cells. MTT assay confirmed that 2-(3-fluorophenylamino)-5-(3-hydroxyphenyl)-1,3,4-thiadiazole (2), 2-(4-bromophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (3), 2-(4-fluorophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (4), had ability to inhibit MCF-7 and MDA-MB-231 cells proliferation. The IC 50 values for the mentioned compounds ranged between 120 and 160 mM (with respect to MCF-7 cells) and from 70 to 170 mM (with respect to MDA-MB-231 cells). It turned out, moreover, that compound 2 is a human topoisomerase II (topoII) catalytic inhibitor whereas the two other compounds (i.e. 3 and 4) are capable of stabilizing DNA-topoII cleavage complex and thus are topoII poisons.

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“…Although a number of reports are available on biological activity of thiosemicarbazides, study on topoisomerase activity is still scarcely explored. The chemotherapeutic potential of DNA topoisomerase inhibitors has been clearly established in recent years [3][4][5] . The antitumor properties of several clinically used drugs (e.g.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity and topoisomerase I/II inhibition activity of novel 4-aryl/alkyl-1-(piperidin-4-yl)-carbonylthiosemicarbazides and 4-benzoylthiosemicarbazides

Siwek

Bielawska²,

Maciorkowska³

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of eight thiosemicarbazide derivatives was examined for cytotoxicity in breast cancer cell cultures. Among them, 4-benzoylthiosemicarbazides proved to be only slightly less potent than chlorambucil in both MDA-MB-231 and MCF-7 lines. In contrast, 4-aryl/ alkylthiosemicarbazides revealed significantly lower cytotoxicity effect. Subsequently, all titled compounds were tested as potential human topoisomerase I and II (topo I and topo II) inhibitors. Mechanistic studies revealed that tested thiosemicarbazides act as both topoisomerase I and topoisomerase II inhibitors. Among them, the best inhibitory activity was found for 4-benzoylthiosemicarbazides (1 and 2) with IC 50 at 50 mM against topo II.

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Catalytic topoisomerase II inhibitors in cancer therapy

Cited by 352 publications

References 80 publications

Resveratrol acts as a topoisomerase II poison in human glioma cells

Resveratrol acts as a topoisomerase II poison in human glioma cells

Search for human DNA topoisomerase II poisons in the group of 2,5-disubstituted-1,3,4-thiadiazoles

Cytotoxicity and topoisomerase I/II inhibition activity of novel 4-aryl/alkyl-1-(piperidin-4-yl)-carbonylthiosemicarbazides and 4-benzoylthiosemicarbazides

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