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Copper(II) complexes with naringenin and hesperetin: cytotoxic activity against A 549 human lung adenocarcinoma cells and investigation on the mode of action

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Abstract

Copper(II) complexes [Cu(H 2 O) 2 (L1)(phen)](ClO 4 ) (1) and [Cu(H 2 O)(L2)(phen)](ClO 4 ) (2) (HL1 = naringenin; HL2 = hesperetin) were obtained, in which an anionic flavonoid ligand is attached to the metal center along with 1,10-phenanthroline (phen) as co-ligand. Complexes (1) and (2) were assayed for their cytotoxic activity against A549 lung carcinoma and against normal lung fibroblasts (LL-24) and human umbilical vein endothelial cells (HUVEC). We found IC50 = 16.42 µM (1) and IC50 = 5.82 µM (2) against A549 tumor cells. Complexes (1) and (2) exhibited slight specificity, being more cytotoxic against malignant than against non-malignant cells. 1 and 2 induced apoptosis on A549 cells in a mitochondria-independent pathway, and showed antioxidant activity. The antioxidant effect of the complexes could possibly improve their apoptotic action, most likely by a PI3K-independent reduction of autophagy. Complexes (1) and (2) interact in vitro with calf thymus DNA by an intercalative binding mode. EPR data indicated that 1 and 2 interact with human serum albumin (HSA) forming mixed ligand species.

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Acknowledgments

The authors are grateful to CNPq, INCT-INOFAR (Proc. CNPq 573.364/2008-6), CAPES PEC-PG and FAPESP (Grants: 2013/07273-2 and 2009/54599-5).

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Authors and Affiliations

  1. Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil

    Lenka V. Tamayo, Ligiane R. Gouvea, Anna C. Sousa, Ronniel M. Albuquerque & Heloisa Beraldo

  2. Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil

    Sarah Fernandes Teixeira, Ricardo Alexandre de Azevedo & Adilson Kleber Ferreira

  3. Departamento de Física, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, 22653-900, Brazil

    Sonia R. W. Louro

  4. Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713, The Netherlands

    Adilson Kleber Ferreira

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  1. Lenka V. Tamayo
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  2. Ligiane R. Gouvea
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Correspondence to Heloisa Beraldo.

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Tamayo, L.V., Gouvea, L.R., Sousa, A.C. et al. Copper(II) complexes with naringenin and hesperetin: cytotoxic activity against A 549 human lung adenocarcinoma cells and investigation on the mode of action. Biometals 29, 39–52 (2016). https://doi.org/10.1007/s10534-015-9894-0

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