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

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 (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.

Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression

“…DNA DSB damage directly induced by BNIPDaCHM is the key component in the toxicity of BNIPDaCHM in MDA-MB-231 cells. This mechanism is also consistent with other novel naphthalimide [35] and bisnaphthalimide derivatives [16,24].…”

“…) -reduced the flexibility of the linker -but enhanced cellular uptake and biological activity in vitro against MDA-MB-231 cells [20]. Even though DNA is considered to be intrinsic to bisnaphthalimide derivative efficacy as observed in colon cancer cells [8,22,23,24];…”

South Yorkshire Cohort: a 'cohort trials facility' study of health and weight - Protocol for the recruitment phase

“…Body Mass Index (BMI) is calculated from patient's self-reported height and weight. Information on waist to height ratio is a better predictor of chronic diseases than BMI for many patients [14], thus patients are also asked to report their waist measurement (a paper tape measure is included with the Health Questionnaire). Ethnicity is collected using the 17 Census 2001 categories in line with the Race Relations (Amendment) Act 2000 which requires public bodies to take account of race equality in policy making and service delivery.…”

Novel Synthetic Approaches for Bisnaphthalimidopropyl (BNIP) Derivatives as Potential Anti-Parasitic Agents for the Treatment of Leishmaniasis

“…Beside targeting the sirtuins, BNIP derivatives strongly interact with DNA-a property of naphtalimides [21]-which makes them a good drug candidate as an anticancer agent [16,[22][23][24][25][26][27]. Naphthalimide planar aromatic rings of BNIP intercalate between DNA base pairs and distort the DNA backbone conformation by interfering with DNA-protein interactions [28,29].…”