title: Alpha, beta-unsaturated lactones 2-furanone and 2-pyrone induce cellular DNA damage, formation of topoisomerase I- and II-DNA complexes and cancer cell death.
abstract: The alpha, beta-unsaturated lactones 2-furanone and 2-pyrone are part of the chemical structure of a variety of naturally occurring compounds (e.g., cardenolides, bufadienolides, acetogenins, coumarins, and food-flavoring furanones), some of which have shown anticancer activity and/or DNA damaging effects. Here we report that 2-furanone and 2-pyrone induce cellular DNA damage (assessed by the comet assay and the gamma-H2AX focus assay) and the formation of topoisomerase I- and topoisomerase II-DNA complexes in cells (visualized and quantified in situ by the TARDIS assay). Cells mutated in BRCA2 (deficient in homologous recombination repair) were significantly hypersensitive to the cytotoxic activity of 2-pyrone, therefore suggesting that BRCA2 plays an important role in the repair of DNA damage induced by this lactone. Both lactones were cytotoxic in A549 lung cancer cells at lower concentrations than in MRC5 non-malignant lung fibroblasts. The possible involvement of 2-furanone and 2-pyrone in the anticancer and DNA-damaging activities of compounds containing these lactones is discussed.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Calderón-Montaño
authors.forename: Estefanía
authors.initials: E
authors.lastname: Burgos-Morón
authors.forename: Manuel Luis
authors.initials: ML
authors.lastname: Orta
authors.forename: Nuria
authors.initials: N
authors.lastname: Pastor
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Austin
authors.forename: Santiago
authors.initials: S
authors.lastname: Mateos
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Lázaro
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000633:toxicity; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects; D024682:BRCA2 Protein / Q000235:genetics; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors; D016650:Fluorescein-5-isothiocyanate; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D006801:Humans; D020014:K562 Cells; D011753:Pyrones / Q000633:toxicity*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: C584017:2-pyrone; D017304:Annexin A5; D024682:BRCA2 Protein; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D011753:Pyrones; D013778:Tetrazolium Salts; D013844:Thiazoles; C004511:butenolide; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C022616:thiazolyl blue; D016650:Fluorescein-5-isothiocyanate; D015107:4-Butyrolactone
keywords: Anticancer; Carcinogenesis; α-Pyrone; γ-Crotonolactone