Resveratrol induces DNA double-strand breaks through human topoisomerase II interaction

Leone, Stefano; Cornetta, Tommaso; Basso, Emiliano; Cozzi, Renata

doi:10.1016/j.canlet.2010.02.022

Cited by 51 publications

(42 citation statements)

References 27 publications

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“…13 Our group previously focused on the effect of RSV treatment on human glioma cells in vitro showing its ability to induce a delay during S phase progression together with the improvement of intercellular junctions. 11,18 Furthermore, we showed its ability in inhibiting in an in vitro test topoisomerase IIa catalytic activity. 11 Topoisomerase II is the primary target for some of the most active drugs currently in use for the treatment of human cancers.…”

Section: Discussionmentioning

confidence: 87%

“…11,18 Furthermore, we showed its ability in inhibiting in an in vitro test topoisomerase IIa catalytic activity. 11 Topoisomerase II is the primary target for some of the most active drugs currently in use for the treatment of human cancers. 29 Among these agents, the so called TOPOpoisons increase the levels of enzyme-DNA cleavable complexes by interacting with topoisomerase II at the protein-DNA interface in a non-covalent manner or covalently modifying the structure of the protein and/or the DNA.…”

Section: Discussionmentioning

confidence: 87%

“…These data are in agreement with what shown by Tyagi et al 31 and ourselves on S phase delay induced by RSV treatment in U87 cells. 11 However, the ability of topoisomerase inhibitors to activate the signalling cascade through ATM pathway is well documented for etoposide. 32 As far as the ATR/Chk1 pathway is concerned, the lack of any increase in the expression of P-ATR is quite surprising.…”

Section: Discussionmentioning

confidence: 99%

“…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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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

“…11 Furthermore, in an in vitro assay, RSV was shown to inhibit the ability of recombinant human TOPOIIa to decatenate kDNA.…”

mentioning

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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“…80,81 This may simultaneously contribute to both the potential anticarcinogenic and carcinogenic properties of the substance in given circumstances.…”

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confidence: 99%

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2015

IJPSR

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ABSTRACT:Resveratrol, an antioxidant found in red wine and certain foods, has been touted as a natural way to slow aging and fight cancer, obesity, heart disease, and diabetes. It also could be accounted as an agent, which has effects to reduced risk of inflammation and blood clotting. In addition there are some studies showing that resveratrol may actually reduce the positive effect of exercise on the heart in older men, but it's important to know that its effects only last a short time after drinking red wine. As promising as it sounds, it is not yet established how resveratrol affects humans, since most studies have been conducted on animals and microbes. Because the information on resveratrol, presented in literature, pointing its health and adverse effects is full with contradictions, especially with respect to the human response, we tried to present the available information with minimal commentary, remaining as neutral as possible and allowing the reader to draw its own conclusion on recommendation of the wide increase usage of resveratrol and a prematurity of such a decision.

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