title: Cu(Nor)2·5H2O, a complex of Cu(II) with Norfloxacin: theoretic approach and biological studies. Cytotoxicity and genotoxicity in cell cultures.
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)·5H(2)O 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)·5H(2)O 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)·5H(2)O 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)·5H(2)O 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)·5H(2)O is a good candidate to be further evaluated for alternative therapeutics in cancer treatment.
authors.affiliation: Cátedra de Bioquímica Patológica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), La Plata, Argentina.
authors.forename: A L
authors.initials: AL
authors.lastname: Di Virgilio
authors.forename: I E
authors.initials: IE
authors.lastname: León
authors.forename: C A
authors.initials: CA
authors.lastname: Franca
authors.forename: I
authors.initials: I
authors.lastname: Henao
authors.forename: G
authors.initials: G
authors.lastname: Tobón
authors.forename: S B
authors.initials: SB
authors.lastname: Etcheverry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D015162:Micronucleus Tests; D056004:Molecular Dynamics Simulation; D009152:Mutagenicity Tests; D009643:Norfloxacin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003300:Copper; D009643:Norfloxacin