title: Copper(II) complexes with naringenin and hesperetin: cytotoxic activity against A 549 human lung adenocarcinoma cells and investigation on the mode of action.
abstract: Copper(II) complexes [Cu(H2O)2 (L1)(phen)](ClO4) (1) and [Cu(H2O)(L2)(phen)](ClO4) (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.
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Lenka V
authors.initials: LV
authors.lastname: Tamayo
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Ligiane R
authors.initials: LR
authors.lastname: Gouvea
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Sousa
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
authors.forename: Ronniel M
authors.initials: RM
authors.lastname: Albuquerque
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.
authors.forename: Sarah Fernandes
authors.initials: SF
authors.lastname: Teixeira
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.
authors.forename: Ricardo Alexandre
authors.initials: RA
authors.lastname: de Azevedo
authors.affiliation: Departamento de Física, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, 22653-900, Brazil.
authors.forename: Sonia R W
authors.initials: SR
authors.lastname: Louro
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, 05508-900, Brazil.|Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713, The Netherlands.
authors.forename: Adilson Kleber
authors.initials: AK
authors.lastname: Ferreira
authors.affiliation: Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil. hberaldo@ufmg.br.
authors.forename: Heloisa
authors.initials: H
authors.lastname: Beraldo
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000008:administration & dosage* / Q000737:chemistry; D003300:Copper / Q000008:administration & dosage* / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000187:drug effects; D044950:Flavanones / Q000008:administration & dosage / Q000737:chemistry; D006569:Hesperidin / Q000008:administration & dosage / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D044950:Flavanones; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; D006569:Hesperidin; C005273:naringenin; C013015:hesperetin
keywords: Copper(II) complexes; Cytotoxic activity; Hesperetin; Mode of action; Naringenin