title: A natural anticancer agent thaspine targets human topoisomerase IB.
abstract: The different steps of the topoisomerase I catalytic cycle have been analyzed in the presence of the plant alkaloid thaspine (1- (2-(Dimethylamino)ethyl)-3,8-dimethoxychromeno[5,4,3-cde]chromene-5,10-dione), known to induce apoptosis in colon carcinoma cells. The experiments indicate that thaspine inhibits both the cleavage and the religation steps of the enzyme reaction. The inhibition is reversible and the effect is enhanced upon pre-incubation. Molecular docking simulations of thaspine over topoisomerase I, in the presence or absence of the DNA substrate, show that thaspine, when interacting with the enzyme alone in the closed or in the open state, can bind in proximity of the active residues preventing the cleavage reaction, whilst when docked with the enzyme-DNA cleavable complex intercalates between the DNA bases in a way similar to that found for camptothecin, explaining its religation inhibition. These results unequivocally demonstrate that thaspine targets human topoisomerase I .
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, Rome 00133, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Castelli
authors.forename: Prafulla
authors.initials: P
authors.lastname: Katkar
authors.forename: Oscar
authors.initials: O
authors.lastname: Vassallo
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D001688:Biological Products; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; C018394:taspine