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Antioxidant, DNA cleavage, and cellular effects of silibinin and a new oxovanadium(IV)/silibinin complex

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Abstract

A new complex of the oxovanadium(IV) cation with the flavolignan silibinin has been synthesized and characterized. Vanadium compounds show interesting biological and pharmacological properties and some of them display antitumoral actions. Flavonoids are part of a larger group of antioxidant compounds called polyphenols which may inhibit the proliferation and growth of cancer cells. The antioxidant and antitumoral effects of silibinin and its oxovanadium(IV) complex were investigated. Silibinin acted as a very strong antioxidant and its complexation with oxovanadium(IV) improved this behavior. Besides, the generation of reactive oxygen species (ROS) by this compound was favored in tumoral (UMR106) cells and correlated with the deleterious behavior in the proliferation of this cell line. Conversely, silibinin did not exert any effect on the proliferation of normal osteoblasts (MC3T3E1). The cytotoxic action and ROS generation of the oxovanadium(IV) complex was more effective in tumoral cells. This behavior was not consistent with cleaving DNA of plasmid DNA pA1 because no significant cleaving activity was observed in both cases. These results suggest that the main deleterious mechanisms may take place through cytotoxic effects more than genotoxic actions. A comparison with our own findings on the behavior of other flavonoids and their vanadyl(IV) complex has also been performed.

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Abbreviations

AAPH:

2,2′-Azobis(2-methylpropionamidine) dihydrochloride

ABTS:

2,2′-Azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) diammonium salt

AGE:

Agarose gel electrophoresi

bp:

Base pair

DHR:

Dihydrorhodamine

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

DPPH· :

1,1-Diphenyl-2-picrylhydrazyl

EDTA:

Ethylenediaminetetraacetic acid

FBS:

Fetal bovine serum

FTIR:

Fourier transform infrared

MOPS:

3-(N-Morpholino)propanesulfonic acid

MPA:

Mercaptopropionic acid

NADH:

Reduced nicotinamide adenine dinucleotide

NBT:

Nitroblue tetrazolium

ORAC:

Oxygen radical absorbance capacity

PBS:

Phosphate-buffered saline

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TEAC:

Trolox-equivalent antioxidant coefficient

VOsil:

Na2[VO(silibinin)2]·6H2O

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Acknowledgments

This work was supported by UNLP, CONICET (PIP1125), ANPCyT (PICT 2008-2218), and CICPBA. E.G.F. and S.B.E. are members of the Carrera del Investigador CONICET. P.A.M.W. is a member of the Carrera del Investigador CICPBA, Argentina. L.N. holds a fellowship from CONICET.

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Authors and Affiliations

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

    Luciana G. Naso, Evelina G. Ferrer, Susana B. Etcheverry & Patricia A. M. Williams

  2. Departamento de Química, Bioquímica e Farmácia, Universidade do Algarve, Campus de Gambelas, 8005-139, Faro, Portugal

    Nataliya Butenko

  3. Centro de Química Estrutural, Instituto Superior Técnico, TU Lisbon, Av Rovisco Pais, 1049-001, Lisbon, Portugal

    Nataliya Butenko & Isabel Cavaco

  4. Departamento de Química Inorgánica, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Apdo 644, 48080, Bilbao, Spain

    Luis Lezama & Teófilo Rojo

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

    Susana B. Etcheverry

Authors
  1. Luciana G. Naso
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  2. Evelina G. Ferrer
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  3. Nataliya Butenko
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  4. Isabel Cavaco
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  5. Luis Lezama
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  7. Susana B. Etcheverry
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  8. Patricia A. M. Williams
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Correspondence to Patricia A. M. Williams.

Electronic supplementary material

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775_2011_769_MOESM1_ESM.pdf

Figure S1. Agarose gel electrophoresis of plasmid DNA after digestion with VOsil, with and without activating agents. Solutions were buffered at pH 7.0 with MOPS. Lanes 1, 11 – controls for native DNA; 2, 10 - controls for linearized DNA (after digestion with VO(acac)2 50μM under phosphate buffer); 3 – VOsil 25 μM; 4 – VOsil 50 μM; 5 – VOsil 50μM + MPA; 6 – VOsil 50 μM + oxone; 7, 8 – controls for MPA and oxone, respectively; 9 – digestion with silibinin 100 μM. The graphic shows the percentage of each form of DNA (Sc – supercoiled, Nck – nicked, Lin – linear) obtained from the gel by densitometry. (PDF 95 kb)

775_2011_769_MOESM2_ESM.pdf

Figure S2. - Agarose gel electrophoresis of plasmid DNA after digestion with VOsil, with increasing complex concentration and in the presence of activating agents. Solutions were buffered at pH 7.0 with phosphate buffer. Lane 1 – control for native DNA; 2 – control for linearized DNA (after digestion with VO(acac)2 50μM under phosphate buffer); 3 - VOsil 6 μM; 4 - VOsil 12 μM; 5 - VOsil 25 μM; 6 - VOsil 50 μM; 7 - VOsil 50 μM + MPA; 8 – VOsil 50 μM + oxone; 9, 10 – controls for MPA and oxone, respectively; 11 – digestion with silibinin 100 μM. The graphic shows the percentage of each form of DNA (Sc – supercoiled, Nck – nicked, Lin – linear) obtained from the gel by densitometry. (PDF 194 kb)

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Naso, L.G., Ferrer, E.G., Butenko, N. et al. Antioxidant, DNA cleavage, and cellular effects of silibinin and a new oxovanadium(IV)/silibinin complex. J Biol Inorg Chem 16, 653–668 (2011). https://doi.org/10.1007/s00775-011-0769-8

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