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Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents.

ABSTRACT: The potential anticancer effect of fluoroquinolone antibiotics has been recently unveiled and related to their ability to interfere with DNA topoisomerase II. We herein envisioned the design and synthesis of novel Ciprofloxacin and Norfloxacin nitric oxide (NO) photo-donor hybrids to explore the potential synergistic antitumor effect exerted by the fluoroquinolone scaffold and NO eventually produced upon light irradiation. Anticancer activity, evaluated on a panel of tumor cell lines, showed encouraging results with IC₅₀ values in the low micromolar range. Some compounds displayed intense antiproliferative activity on triple-negative and doxorubicin-resistant breast cancer cell lines, paving the way for their potential use to treat aggressive, refractory and multidrug-resistant breast cancer. No significant additive effect was observed on PC3 and DU145 cells following NO release. Conversely, antimicrobial photodynamic experiments on both Gram-negative and Gram-positive microorganisms displayed a significant killing rate in Staphylococcus aureus, accounting for their potential effectiveness as selective antimicrobial photosensitizers.

SUBMITTER: Fallica AN

PROVIDER: S-EPMC8389907 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents.

Fallica Antonino Nicolò AN Barbaraci Carla C Amata Emanuele E Pasquinucci Lorella L Turnaturi Rita R Dichiara Maria M Intagliata Sebastiano S Gariboldi Marzia Bruna MB Marras Emanuela E Orlandi Viviana Teresa VT Ferroni Claudia C Martini Cecilia C Rescifina Antonio A Gentile Davide D Varchi Greta G Marrazzo Agostino A

Journal of medicinal chemistry 20210728 15

The potential anticancer effect of fluoroquinolone antibiotics has been recently unveiled and related to their ability to interfere with DNA topoisomerase II. We herein envisioned the design and synthesis of novel Ciprofloxacin and Norfloxacin nitric oxide (NO) photo-donor hybrids to explore the potential synergistic antitumor effect exerted by the fluoroquinolone scaffold and NO eventually produced upon light irradiation. Anticancer activity, evaluated on a panel of tumor cell lines, showed enc ...[more]

PMID: 34319100

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Project description:PurposeAnticancer drug delivery systems are often limited by hurdles, such as off-target distribution, slow cellular internalization, limited lysosomal escape, and drug resistance. To overcome these limitations, we have developed a stable nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle (SMA-Dox) carrier.Materials and methodsEffects of SMA-tDodSNO and/or in combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial membrane potential, lysosomal membrane permeability, tumor tissue, and tumor growth were studied using in vitro and in vivo model of triple-negative breast cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination with SMA-tDodSNO were measured in cells and tumor tissues.ResultsCombination of SMA-tDodSNO and Dox synergistically decreased cell viability and induced apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 µM) significantly enhanced the cellular uptake of SMA-Dox and increased Dox concentration in the cells resulting in a twofold increase (P<0.001). Lysosomal membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 40 µM SMA-tDodSNO (P<0.05 vs control) and when combined with SMA-Dox, this effect was significantly potentiated (P<0.001 vs SMA-Dox). Subcutaneous administration of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the control group. SMA-tDodSNO in combination with SMA-Dox resulted in a statistically significant 4.7-fold reduction in the tumor volume (P<0.001 vs control), without causing significant toxicity as monitored through body weight loss.ConclusionTaken together, these results suggest that SMA-tDodSNO can be used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a model of TNBC.

Dataset Information

Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents.

Publications

Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents.

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