title: The influence of bisnaphthalimidopropyl polyamines on DNA instability and repair in Caco-2 colon epithelial cells.
abstract: Bisnaphthalimido compounds bis-intercalate to DNA via the major groove and are potentially potent cancer therapeutics. Previously, we incorporated natural polyamines as linkers connecting the two naphthalimido ring moieties to create a series of soluble bisnaphthalimidopropyl polyamines (BNIPPs). Here, extending earlier work on bisnaphthalimidopropylspermidine (BNIPSpd)-induced apoptosis in colon adenocarcinoma Caco-2 cells, we compare the cytotoxicity and genotoxicity of BNIPSpd relative to the spermine and oxaspermine derivatives, bisnaphthalimidopropylspermine (BNIPSpm) and bisnaphthalimidopropyloxaspermine (BNIPOSpm). The order of cytotoxicity after 24 h was BNIPSpd (IC(50) = 0.47 μM) > BNIPSpm (IC(50) = 10.04 μM) > BNIPOSpm (IC(50) >50 μM). After a 72-h BNIPOSpm exposure, an IC(50) = 10.25 μM was achieved. With 4-h exposure to BNIPSpd or BNIPSpm or 12-h exposure to BNIPOSpm, concentrations ≥1 μM induced a significant dose-dependent increase in DNA damage as measured by alkaline single-cell gel electrophoresis. The longer incubation times required for BNIPOSpm to induce DNA strand breaks reflect a slower rate of BNIPOSpm cellular distribution as monitored via BNIPP fluorescence within the cells. Moreover, exposure to a non-genotoxic concentration of BNIPSpd, BNIPSpm (0.1 μM for 4 h) or BNIPOSpm (0.1 μM for 12 h) induced a significant decrease in repair of oxidative DNA damage induced by hydrogen peroxide. In conclusion, BNIPP exposure in Caco-2 cells is associated with significant induction of DNA damage and inhibition of DNA repair at non-genotoxic concentrations. The latter is a novel consequence of BNIPP-cell interactions which adds to the spectrum of therapeutically relevant activities that may be exploited for the design and development of naphthalimide-based therapeutics.
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Scotland, UK. c.bestwick@abdn.ac.uk
authors.forename: Charles Stuart
authors.initials: CS
authors.lastname: Bestwick
authors.forename: Lynda D
authors.initials: LD
authors.lastname: Ralton
authors.forename: Lesley
authors.initials: L
authors.lastname: Milne
authors.forename: Paul
authors.initials: P
authors.lastname: Kong Thoo Lin
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Duthie
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020552:Comet Assay; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D053644:Naphthalimides / Q000138:chemical synthesis / Q000494:pharmacology*; D010084:Oxidation-Reduction; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D007364:Intercalating Agents; D053644:Naphthalimides; D015363:Quinolones; C504604:bisnaphthalimidopropyl spermine; D013096:Spermine; D004247:DNA; D006861:Hydrogen Peroxide