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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

Lookup NU author(s): Professor Caroline Austin, Dr Miguel Lopez-Lazaro

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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 IIDNA 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.


Publication metadata

Author(s): Calderon-Montano JM, Burgos-Moron E, Orta ML, Pastor N, Austin CA, Mateos S, Lopez-Lazaro M

Publication type: Article

Publication status: Published

Journal: Toxicology Letters

Year: 2013

Volume: 222

Issue: 1

Pages: 64-71

Print publication date: 15/07/2013

ISSN (print): 0378-4274

ISSN (electronic): 1879-3169

Publisher: Elsevier Ireland

URL: http://dx.doi.org/10.1016/j.toxlet.2013.07.007

DOI: 10.1016/j.toxlet.2013.07.007


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