NDLI: The influence of bisnaphthalimidopropyl polyamines on DNA instability and repair in Caco-2 colon epithelial cells

Content Provider	Springer Nature Link
Author	Bestwick, Charles Stuart Ralton, Lynda D. Milne, Lesley Kong Thoo Lin, Paul Duthie, Susan J.
Copyright Year	2011
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 (IC50 = 0.47 μM) > BNIPSpm (IC50 = 10.04 μM) > BNIPOSpm (IC50 >50 μM). After a 72-h BNIPOSpm exposure, an IC50 = 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.
Starting Page	455
Ending Page	463
Page Count	9
File Format	PDF
ISSN	07422091
Journal	Cell Biology and Toxicology
Volume Number	27
Issue Number	6
e-ISSN	15736822
Language	English
Publisher	Springer Netherlands
Publisher Date	2011-08-13
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	Bisnaphthalimides Bisnaphthalimidopropyl polyamines Cytotoxicity Chemotherapy DNA damage DNA repair Biochemistry Cell Biology Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Health, Toxicology and Mutagenesis Toxicology

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