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 mu M)>BNIPSpm (IC50=10.04 mu M)>BNIPOSpm (IC50 >50 mu M). After a 72-h BNIPOSpm exposure, an IC50=10.25 mu M was achieved. With 4-h exposure to BNIPSpd or BNIPSpm or 12-h exposure to BNIPOSpm, concentrations >= 1 mu M 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 mu M for 4 h) or BNIPOSpm (0.1 mu M 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.
Original language | English |
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Pages (from-to) | 455-463 |
Number of pages | 9 |
Journal | Cell Biology and Toxicology |
Volume | 27 |
Issue number | 6 |
Early online date | 13 Aug 2011 |
DOIs | |
Publication status | Published - Dec 2011 |
Keywords
- bisnaphthalimides
- bisnaphthalimidopropyl polyamines
- cytotoxicity
- chemotherapy
- DNA damage
- DNA repair
- antitumor agents
- topoisomerase-II
- breast-cancer
- in-vitro
- Biological evaluation
- binding properties
- phase-II
- derivatives
- damage
- naphthalimide