title: A novel carbohydrate derived compound FCP5 causes DNA strand breaks and oxidative modifications of DNA bases in cancer cells.
abstract: 1,5-Anhydro-6-deoxy-methane-sulfamido-D-glucitol (FCP5) is a functionalized carbohydrate containing functional groups that render it potentially therapeutically useful. According to our concept of 'functional carb-pharmacophores' (FCPs) incorporation of the methanesulfonamido pharmacophore to 1,5 glucitol could create a therapeutically useful compound. Our previous studies revealed that FCP5 was cytotoxic to cancer cells. Therefore, in this work we assessed the cytotoxic mechanisms of FCP5 in four cancer cell lines - HeLa, LoVo, A549 and MCF-7, with particular focus on DNA damage and repair. A broad spectrum of methods, including comet assay with modifications, DNA repair enzyme assay, plasmid relaxation assay, and DNA fragmentation assay, were used. We also checked the potential for FCP5 to induce apoptosis. The results show that FCP5 can induce DNA strand breaks as well as oxidative modifications of DNA bases. DNA lesions induced by FCP5 were not entirely repaired in HeLa cells and DNA repair kinetics differs from other cell lines. Results from molecular docking and plasmid relaxation assay suggest that FCP5 binds to the major groove of DNA with a preference for adenosine-thymine base pair sequences and directly induces DNA strand breaks. Thus, FCP5 may represent a novel lead for the design of new major groove-binding compounds. The results also confirmed the validity of functional carb-pharmacophores as a new source of innovative drugs.
authors.affiliation: Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland. Electronic address: acz@biol.uni.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Czubatka
authors.affiliation: Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland. Electronic address: jsarnik@biol.uni.lodz.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sarnik
authors.affiliation: Division of Engineering and Physics, Wilkes University, 84 W. South Street, Wilkes-Barre, PA 18766, USA. Electronic address: del.lucent@wilkes.edu.
authors.forename: Del
authors.initials: D
authors.lastname: Lucent
authors.affiliation: Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland. Electronic address: jblasiak@biol.uni.lodz.pl.
authors.forename: Janusz
authors.initials: J
authors.lastname: Blasiak
authors.affiliation: Department of Pharmaceutical Sciences, Nesbitt School of Pharmacy, Wilkes University, 84 W. South Street, Wilkes-Barre, PA 18766, USA. Electronic address: zbigniew.witczak@wilkes.edu.
authors.forename: Zbigniew J
authors.initials: ZJ
authors.lastname: Witczak
authors.affiliation: Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland. Electronic address: tomasz.poplawski@biol.uni.lodz.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Poplawski
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D009690:Nucleic Acid Conformation; D018384:Oxidative Stress / Q000187:drug effects*; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000596776:1,5-anhydro-6-deoxymethanesulfamidoglucitol; D002241:Carbohydrates; D013449:Sulfonamides; D013012:Sorbitol; D004247:DNA
keywords: 1,5-Anhydro-6-deoxy-methane-sulfamido-d-glucitol; Comet assay; DNA damage; DNA repair; Functional carb-pharmacophores; Genotoxicity