Rowett Institute of Nutrition and Health, University of Aberdeen, Scotland, UK.
Cell Biol Toxicol. 2011 Dec;27(6):455-63. doi: 10.1007/s10565-011-9199-1. Epub 2011 Aug 13.
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.
双萘酰亚胺化合物通过主沟双插入 DNA，并且可能是潜在的有效的癌症治疗药物。以前，我们将天然多胺作为连接两个萘酰亚胺环部分的连接物，合成了一系列可溶性的双萘酰亚胺丙基多胺（BNIPPs）。在这里，我们扩展了早期关于双萘酰亚胺丙基精脒（BNIPSpd）在结肠腺癌 Caco-2 细胞中诱导细胞凋亡的研究，比较了 BNIPSpd 相对于精脒和奥沙精脒衍生物，双萘酰亚胺丙基精脒（BNIPSpm）和双萘酰亚胺丙基奥沙精脒（BNIPOSpm）的细胞毒性和遗传毒性。24 h 后的细胞毒性顺序为 BNIPSpd（IC50=0.47 μM）>BNIPSpm（IC50=10.04 μM）>BNIPOSpm（IC50>50 μM）。BNIPOSpm 暴露 72 h 后，IC50 达到 10.25 μM。BNIPSpd 或 BNIPSpm 暴露 4 h 或 BNIPOSpm 暴露 12 h 后，浓度≥1 μM 可显著诱导碱性单细胞凝胶电泳测量的 DNA 损伤的剂量依赖性增加。BNIPOSpm 诱导 DNA 链断裂所需的较长孵育时间反映了 BNIPOSpm 细胞内分布的较慢速度，这可通过细胞内 BNIPP 荧光监测来反映。此外，暴露于非遗传毒性浓度的 BNIPSpd、BNIPSpm（4 h 时 0.1 μM）或 BNIPOSpm（12 h 时 0.1 μM）可显著降低过氧化氢诱导的氧化 DNA 损伤的修复。总之，Caco-2 细胞中 BNIPP 的暴露与非遗传毒性浓度下显著诱导 DNA 损伤和抑制 DNA 修复有关。后者是 BNIPP-细胞相互作用的新后果，增加了可能被用于设计和开发萘酰亚胺类治疗药物的治疗相关活性的范围。
