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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Abbreviations
- BNIPSpd:
-
Bisnaphthalimidopropylspermidine
- BNIPSpm:
-
Bisnaphthalimidopropylspermine
- BNIPOSpm:
-
Bisnaphthalimidopropyloxaspermine
- SCGE:
-
Single-cell gel electrophoresis
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This work was supported by the School of Pharmacy and Life Sciences, The Robert Gordon University Aberdeen and by the Scottish Government (RINH).
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Bestwick, C.S., Ralton, L.D., Milne, L. et al. The influence of bisnaphthalimidopropyl polyamines on DNA instability and repair in Caco-2 colon epithelial cells. Cell Biol Toxicol 27, 455–463 (2011). https://doi.org/10.1007/s10565-011-9199-1
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DOI: https://doi.org/10.1007/s10565-011-9199-1