title: Resveratrol acts as a topoisomerase II poison in human glioma cells.
abstract: 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 γH2AX expression in U87 glioma cells. Furthermore, we showed that it inhibits the ability of recombinant human topoisomerase IIα 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 IIα 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 γH2AX. 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 TOPOIIα so inducing DNA damage; ATM, Chk2 and γH2AX are involved in the DNA damage signalling after RSV treatment.
authors.affiliation: Department of Biology, University Roma TRE, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Leone
authors.forename: Emiliano
authors.initials: E
authors.lastname: Basso
authors.forename: Fabio
authors.initials: F
authors.lastname: Polticelli
authors.forename: Renata
authors.initials: R
authors.lastname: Cozzi
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D013267:Stilbenes; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D004250:DNA Topoisomerases, Type II; D000077185:Resveratrol