title: Effects of Olive Metabolites on DNA Cleavage Mediated by Human Type II Topoisomerases.
abstract: Several naturally occurring dietary polyphenols with chemopreventive or anticancer properties are topoisomerase II poisons. To identify additional phytochemicals that enhance topoisomerase II-mediated DNA cleavage, a library of 341 Mediterranean plant extracts was screened for activity against human topoisomerase IIα. An extract from Phillyrea latifolia L., a member of the olive tree family, displayed high activity against the human enzyme. On the basis of previous metabolomics studies, we identified several polyphenols (hydroxytyrosol, oleuropein, verbascoside, tyrosol, and caffeic acid) as potential candidates for topoisomerase II poisons. Of these, hydroxytyrosol, oleuropein, and verbascoside enhanced topoisomerase II-mediated DNA cleavage. The potency of these olive metabolites increased 10-100-fold in the presence of an oxidant. Hydroxytyrosol, oleuropein, and verbascoside displayed hallmark characteristics of covalent topoisomerase II poisons. (1) The activity of the metabolites was abrogated by a reducing agent. (2) Compounds inhibited topoisomerase II activity when they were incubated with the enzyme prior to the addition of DNA. (3) Compounds were unable to poison a topoisomerase IIα construct that lacked the N-terminal domain. Because hydroxytyrosol, oleuropein, and verbascoside are broadly distributed across the olive family, extracts from the leaves, bark, and fruit of 11 olive tree species were tested for activity against human topoisomerase IIα. Several of the extracts enhanced enzyme-mediated DNA cleavage. Finally, a commercial olive leaf supplement and extra virgin olive oils pressed from a variety of Olea europea subspecies enhanced DNA cleavage mediated by topoisomerase IIα. Thus, olive metabolites appear to act as topoisomerase II poisons in complex formulations intended for human dietary consumption.
authors.forename: Kendra R
authors.initials: KR
authors.lastname: Vann
authors.forename: Carl A
authors.initials: CA
authors.lastname: Sedgeman
authors.affiliation: ∥Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.|⊥Department of Oncology, Soroka University Medical Center, Beer Sheva 84105, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Gopas
authors.affiliation: @The Jacob Blaustein Institutes for Desert Research (BIDR), French Associates Institute for Agriculture and Biotechnology of Drylands, Ben-Gurion University of the Negev, Sede Boqer Campus, Beer Sheva 84990, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Golan-Goldhirsh
authors.affiliation: §VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
mesh_terms: D053837:DNA Cleavage; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005638:Fruit / Q000737:chemistry; D005960:Glucosides / Q000737:chemistry; D006801:Humans; D057888:Iridoid Glucosides; D039823:Iridoids / Q000737:chemistry; D031658:Olea / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000737:chemistry; D024301:Plant Bark / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry*; D018515:Plant Leaves / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000737:chemistry*; D059808:Polyphenols
chemical_list: D004250:DNA Topoisomerases, Type II; D005960:Glucosides; D057888:Iridoid Glucosides; D039823:Iridoids; D010636:Phenols; D010626:Phenylethyl Alcohol; D010936:Plant Extracts; D059005:Topoisomerase II Inhibitors; C005975:3,4-dihydroxyphenylethanol; C002769:oleuropein; C058956:acteoside; D059808:Polyphenols