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Olive Leaf Metabolites as Covalent Human Topoisomerase II Poisons
Author(s) -
Vann Kendra R,
Sedgeman Carl A,
Gopas Jacob,
GolanGoldhirsh Avi,
Osheroff Neil
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1047.2
Subject(s) - topoisomerase , oleuropein , hydroxytyrosol , biochemistry , dna , verbascoside , enzyme , dna damage , biology , chemistry , antioxidant , polyphenol , stereochemistry , glycoside
Topoisomerase II plays many essential roles in genome maintenance. To carry out its physiological functions, the enzyme generates transient double‐stranded breaks in the DNA to help resolve topological problems that naturally occur. Thus, while essential to cell survival, topoisomerase II has the potential to fragment the genome. Beyond its critical cellular functions, human topoisomerase II is the target for a number of widely prescribed anticancer drugs that act by increasing levels of enzyme‐mediated DNA strand breaks. Many of these “topoisomerase II poisons” are derived from natural sources. Identification and characterization of topoisomerase II poisons from natural sources can provide novel drug scaffolds. Therefore, a series of water‐soluble extracts from Mediterranean plants were screened for activity against human topoisomerase IIα. An extract from Phillyrhea latifolia L., a member of the olive tree family, significantly enhanced DNA cleavage mediated by human topoisomerase IIα . P. latifolia L. contains a number of phenolic metabolites, including antioxidants associated with several human health benefits. Oleuropein, hydroxytyrosol, and verbascoside enhanced topoisomerase IIα‐mediated DNA cleavage ~4‐fold. Analysis of topoisomerase II‐mediated DNA cleavage carried out in the presence of oleuropein, hydroxytyrosol, and verbascoside indicated that these compounds displayed hallmark characteristics of “covalent topoisomerase II poisons.” First, the ability of the metabolites to poison topoisomerase II was enhanced substantially in the presence of an oxidant, but was abrogated in the presence of a reducing agent. Second, the metabolites required the N‐terminal region of topoisomerase IIα to enhance DNA cleavage. Third, the metabolites inhibited topoisomerase II activity when incubated with the enzyme prior to the addition of DNA. Phenolic olive plant metabolites retained the ability to act as topoisomerase IIα poisons in complex dietary herbal formulations, such as commercial olive leaf extracts and extra virgin olive oils. These results strongly suggest that olive plant metabolites can act as dietary topoisomerase II poisons. These studies may provide a platform for developing new anticancer or chemopreventative therapies. Current studies are focused on further elucidating the interaction of covalent poisons with topoisomerase II. Results from ongoing mutagenesis studies may provide additional insight into the mechanism by which covalent poisons interact with human topoisomerase II. Support or Funding Information GM033944, GM062459, GM08320, ICA (Israel), Deutsche Forschungsgemeinschaft, and R. H. Holzer Foundation.