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Antiproliferative and apoptosis-inducing activity of an oxidovanadium(IV) complex with the flavonoid silibinin against osteosarcoma cells

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Abstract

Flavonoids are a large family of polyphenolic compounds synthesized by plants. They display interesting biological effects mainly related to their antioxidant properties. On the other hand, vanadium compounds also exhibit different biological and pharmacological effects in cell culture and in animal models. Since coordination of ligands to metals can improve or change the pharmacological properties, we report herein, for the first time, a detailed study of the mechanisms of action of an oxidovanadium(IV) complex with the flavonoid silibinin, Na2[VO(silibinin)2]·6H2O (VOsil), in a model of the human osteosarcoma derived cell line MG-63. The complex inhibited the viability of osteosarcoma cells in a dose-dependent manner with a greater potency than that of silibinin and oxidovanadium(IV) (p < 0.01), demonstrating the benefit of complexation. Cytotoxicity and genotoxicity studies also showed a concentration effect for VOsil. The increase in the levels of reactive oxygen species and the decrease of the ratio of the amount of reduced glutathione to the amount of oxidized glutathione were involved in the deleterious effects of the complex. Besides, the complex caused cell cycle arrest and activated caspase 3, triggering apoptosis as determined by flow cytometry. As a whole, these results show the main mechanisms of the deleterious effects of VOsil in the osteosarcoma cell line, demonstrating that this complex is a promising compound for cancer treatments.

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Acknowledgments

This work was partly supported by UNLP (11X/554), CONICET (PIP 1125), and ANPCyT (PICT 2008-2218 and PICT-2010-0981) from Argentina. A.L.D.V.and S.B.E. are members of the Carrera del Investigador, CONICET, Argentina. P.A.M.W. is member of the Carrera del Investigador, CIC, and PBA. I.E.L. has a fellowship from ANPCyT, Argentina, and a fellowship from AMSUD- PASTEUR, Institut Pasteur, Uruguay. L.G.N. has a postdoctoral fellowship from CONICET, Argentina. V.P. and M.B.F. are members of the Sistema Nacional de Investigadores of the Agencia Nacional de Investigación e Innovación in Uruguay. The authors would like to thank Inés Tiscornia for the management work with the cells and Miguel Reigosa for help with the PMBC assay. Moreover, the authors would like to thank M.C. Bernal for her careful revision of the manuscript.

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Authors and Affiliations

  1. Catedra de Bioquímica Patológica, Facultad Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900, La Plata, Argentina

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

  2. Centro de Química Inorgánica (CEQUINOR) Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900, La Plata, Argentina

    I. E. Leon, A. L. Di Virgilio, L. G. Naso, P. A. M. Williams & S. B. Etcheverry

  3. Unidad de Biología Celular, Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay

    V. Porro & M. Bollati-Fogolín

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  1. I. E. Leon
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  2. V. Porro
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  3. A. L. Di Virgilio
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Correspondence to S. B. Etcheverry.

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Leon, I.E., Porro, V., Di Virgilio, A.L. et al. Antiproliferative and apoptosis-inducing activity of an oxidovanadium(IV) complex with the flavonoid silibinin against osteosarcoma cells. J Biol Inorg Chem 19, 59–74 (2014). https://doi.org/10.1007/s00775-013-1061-x

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