title: Iridoids as DNA topoisomerase I poisons.
abstract: The discovery of new topoisomerase I inhibitors is necessary since most of the antitumor drugs are targeted against type II and only a very few can specifically affect type I. Topoisomerase poisons generate toxic DNA damage by stabilization of the covalent DNA-topoisomerase cleavage complex and some have therapeutic efficacy in human cancer. Two iridoids, aucubin and geniposide, have shown antitumoral activities, but their activity against topoisomerase enzymes has not been tested. Here it was found that both compounds are able to stabilize covalent attachments of the topoisomerase I subunits to DNA at sites of DNA strand breaks, generating cleavage complexes intermediates so being active as poisons of topoisomerase I, but not topoisomerase II. This result points to DNA damage induced by topoisomerase I poisoning as one of the possible mechanisms by which these two iridoids have shown antitumoral activity, increasing interest in their possible use in cancer chemoprevention and therapy.
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacognosia, Facultad de Farmacia C/P García González no 2, 41012, Sevilla, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez
authors.forename: Carmen
authors.initials: C
authors.lastname: Martín-Cordero
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Ayuso
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005960:Glucosides / Q000506:poisoning*; D006801:Humans; D057888:Iridoid Glucosides; D039823:Iridoids / Q000506:poisoning*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D011714:Pyrans / Q000506:poisoning*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D005960:Glucosides; D057888:Iridoid Glucosides; D039823:Iridoids; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C007835:geniposide; C006650:aucubin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin