Oxidovanadium(IV) complexes with chrysin and silibinin: anticancer activity and mechanisms of action in a human colon adenocarcinoma model

Abstract

Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal antitumor agents in combination to its low toxicity. On the other hand, flavonoids are a wide family of polyphenolic compounds synthesized by plants that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, a exhaustive study of the mechanisms of action of two oxidovanadium(IV) complexes with the flavonoids: silibinin Na2[VO(silibinin)2]·6H2O (VOsil) and chrysin [VO(chrysin)2EtOH]2 (VOchrys) on human colon adenocarcinoma derived cell line HT-29. The complexes inhibited the cell viability of colon adenocarcinoma cells in a dose dependent manner with a greater potency than that the free ligands and free metal, demonstrating the benefit of complexation. The decrease of the ratio of the amount of reduced glutathione to the amount of oxidized glutathione were involved in the deleterious effects of both complexes. Besides, VOchrys caused cell cycle arrest in G2/M phase while VOsil activated caspase 3 and triggering the cells directly to apoptosis. Moreover, VOsil diminished the NF-kB activation via increasing the sensitivity of cells to apoptosis. On the other hand, VOsil inhibited the topoisomerase IB activity concluding that this is important target involved in the anticancer vanadium effects. As a whole, the results presented herein demonstrate that VOsil has a stronger deleterious action than VOchrys on HT-29 cells, whereby suggesting that Vosil is the potentially best candidate for future use in alternative anti-tumor treatments.

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Acknowledgments

This work was partly supported by UNLP (11X/690), CONICET (PIP 1125), and ANPCyT (PICT 2008-2218) from Argentina, project No 10121 Italian Association for Cancer Research (AIRC). S.B.E. is member of the Carrera del Investigador, CONICET, Argentina. I.E.L. has a fellowship from CONICET, Argentina, and a fellowship from AMSUD- PASTEUR, Institut Pasteur, Uruguay. J.F.C.V has a fellowship from CONICET, Argentina. I.T, V.P. and M.B.F. are members of the Sistema Nacional de Investigadores of the Agencia Nacional de Investigación e Innovación in Uruguay.

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Correspondence to S. B. Etcheverry.

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León, I.E., Cadavid-Vargas, J.F., Tiscornia, I. et al. Oxidovanadium(IV) complexes with chrysin and silibinin: anticancer activity and mechanisms of action in a human colon adenocarcinoma model. J Biol Inorg Chem 20, 1175–1191 (2015). https://doi.org/10.1007/s00775-015-1298-7

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Keywords

  • Metal based drug
  • HT-29 human colon adenocarcinoma cells
  • Mechanisms of action
  • Flavonoids
  • Vanadium