title: Effects of Secondary Metabolites from the Fungus Septofusidium berolinense on DNA Cleavage Mediated by Human Topoisomerase IIα.
abstract: Two metabolites from the ascomycete fungus Septofusidium berolinense were recently identified as having antineoplastic activity [Ekiz et al. (2015) J. Antibiot. , DOI: 10.1038/ja.2015.84]. However, the basis for this activity is not known. One of the compounds [3,6-dihydroxy-2-propylbenzaldehyde (GE-1)] is a hydroquinone, and the other [2-hydroxymethyl-3-propylcyclohexa-2,5-diene-1,4-dione (GE-2)] is a quinone. Because some hydroquinones and quinones act as topoisomerase II poisons, the effects of GE-1 and GE-2 on DNA cleavage mediated by human topoisomerase IIα were assessed. GE-2 enhanced DNA cleavage ∼4-fold and induced scission with a site specificity similar to that of the anticancer drug etoposide. Similar to other quinone-based topoisomerase II poisons, GE-2 displayed several hallmark characteristics of covalent topoisomerase II poisons, including (1) the inability to poison a topoisomerase IIα construct that lacks the N-terminal domain, (2) the inhibition of DNA cleavage when the compound was incubated with the enzyme prior to the addition of plasmid, and (3) the loss of poisoning activity in the presence of a reducing agent. In contrast to GE-2, GE-1 did not enhance DNA cleavage mediated by topoisomerase IIα except at very high concentrations. However, the activity and potency of the metabolite were dramatically enhanced under oxidizing conditions. These results suggest that topoisomerase IIα may play a role in mediating the cytotoxic effects of these fungal metabolites.
authors.forename: Kendra R
authors.initials: KR
authors.lastname: Vann
authors.forename: Güner
authors.initials: G
authors.lastname: Ekiz
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Pamukkale University , 20070 Denizli, Turkey.
authors.forename: Sevil
authors.initials: S
authors.lastname: Zencir
authors.forename: Erdal
authors.initials: E
authors.lastname: Bedir
authors.forename: Zeki
authors.initials: Z
authors.lastname: Topcu
authors.affiliation: VA Tennessee Valley Healthcare System , Nashville, Tennessee 37212, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D001547:Benzaldehydes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003512:Cyclohexanones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053837:DNA Cleavage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005658:Fungi / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D064210:Secondary Metabolism
chemical_list: C000613694:2-hydroxymethyl-3-propylcyclohexa-2,5-diene-1,4-dione; C000613693:3,6-dihydroxy-2-propylbenzaldehyde; D000951:Antigens, Neoplasm; D001547:Benzaldehydes; D003512:Cyclohexanones; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II