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Cu(Nor)2·5H2O, a complex of Cu(II) with Norfloxacin: theoretic approach and biological studies. Cytotoxicity and genotoxicity in cell cultures

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Abstract

Norfloxacin is a fluoroquinolone antibiotic used in the treatment of bacterial infections. In this article, we studied the potential antitumoral action of a complex of Norfloxacin with Cu(II), Cu(Nor)2·5H2O on osteosarcoma cells (UMR106) and calvaria-derived cells (MC3T3-E1), evaluating its cytotoxicity and genitoxicity. We have also elucidated the more stable conformation of this complex under physiologic conditions by Molecular Dynamic simulations based on the model of the canonical ensemble and PM6 force field. When solvent effect was taken into account, the complex conformation with both carbonyl groups in opposite sides displayed lower energy. Cu(Nor)2·5H2O caused an inhibitory effect on the proliferation on both cell lines from 300 μM (P < 0.01). Nevertheless, the decline on cell proliferation of UMR106 cells was more pronounced (45 % vs basal) than in MC3T3-E1 cells (20 % vs basal) at 300 μM (P < 0.01). Cu(Nor)2·5H2O altered lysosomal metabolism (Neutral Red assay) in a dose-dependent manner from 300 μM (P < 0.001). Morphological studies showed important transformations that correlated with a decrease in the number of cells in a dose-dependent manner. Moreover, Cu(Nor)2·5H2O caused statistically significant genotoxic effects on both osteoblast cell lines in a lower range of concentrations (Micronucleus assay) (P < 0.05 at 10 μM, P < 0.001 from 25 to 50 μM). UMR106 cells displayed a dose-related genotoxic effect between 5 and 25 μM while the MC3T3-E1 cells showed a narrower concentration dependent range. Altogether, these results suggest that Cu(Nor)2·5H2O is a good candidate to be further evaluated for alternative therapeutics in cancer treatment.

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Acknowledgments

This work was partly supported by UNLP (11X/554), CONICET (PIP 1125), ANPCyT (PICT 2218 and PICT-2010-0981). The authors would like to thank MINCYT (CO/08/07) from Argentina, and UdeA and COLCIENCIAS from Colombia, for mobility funding. ALDV and SBE are members of the Carrera del Investigador, CONICET, Argentina. IEL is a fellowship from ANPCyT, Argentina.

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Authors and Affiliations

  1. Cátedra de Bioquímica Patológica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), La Plata, Argentina

    A. L. Di Virgilio, I. E. León & S. B. Etcheverry

  2. CEQUINOR (CONICET-UNLP), Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), La Plata, Argentina

    A. L. Di Virgilio, I. E. León, C. A. Franca & S. B. Etcheverry

  3. Departamento de Farmacia, Facultad de Química Farmacéutica, Universidad de Antioquia (UDEA), Antioquia, Colombia

    I. Henao & G. Tobón

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  1. A. L. Di Virgilio
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  2. I. E. León
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  4. I. Henao
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  6. S. B. Etcheverry
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Correspondence to S. B. Etcheverry.

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Di Virgilio, A.L., León, I.E., Franca, C.A. et al. Cu(Nor)2·5H2O, a complex of Cu(II) with Norfloxacin: theoretic approach and biological studies. Cytotoxicity and genotoxicity in cell cultures. Mol Cell Biochem 376, 53–61 (2013). https://doi.org/10.1007/s11010-012-1548-8

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