The influence of bisnaphthalimidopropyl polyamines on DNA instability and repair in Caco-2 colon epithelial cells |
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Authors: | Charles Stuart Bestwick Lynda D Ralton Lesley Milne Paul Kong Thoo Lin Susan J Duthie |
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Institution: | (1) Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Aberdeen, AB21 9SB, Scotland, UK;(2) School of Pharmacy and Life Sciences, The Robert Gordon University, St. Andrew Street, Aberdeen, AB25 1HG, UK |
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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. |
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