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Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases

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Abstract

A new losartan [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol zinc(II) complex [Zn(Los)Cl], was synthesized and characterized. The crystal structure was determined by x-ray diffraction methods. When aqueous solutions of the ligand and the metal were mixed, the known and more soluble powder [Zn(Los)2].3H2O (ZnLos) complex has been obtained. The interactions with phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up to 500 μM concentration: a decrease of the acid phosphatase (AcP) associated with an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO4 showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations higher than 75 μM with reactive oxygen species (ROS) generation and GSH (and GSH/GSSG ratio) depletion. Apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method, a mechanism accompanied by upregulation of BAX protein, downregulation of Bcl-XL and release of caspase-3. The BAX/Bcl-XL ratio was found to be significantly higher in cells exposure to ZnLos than cells treated with ZnSO4, in agreement with the higher apoptotic percentage of cells found for the complex. Cell death was found to be produced by apoptosis and no necrosis has been observed. On the contrary, losartan exerted low effects on phosphatases, produced some reduction of cancer cell viability (concentrations > 250 μM, number of apoptotic cells similar to the basal) with low ROS depletion, without alteration of the GSH/GSSG and low BAX/Bcl-XL ratios. In the MRC-5, normal lung fibroblasts cell line only ZnSO4 at concentrations higher than 200 μM displays cytotoxic effects.

Interaction of Zn with losartan. Activation of intrinsic apoptotic signaling pathway in lung cancer cells and effects on alkaline and acid phosphatases

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Acknowledgements

This work was supported by UNLP, CONICET (PIP 0611), CICPBA (PICyT 813/13), and ANPCyT (PICT-2016-1814, PME06 2804 and PICT06 2315), Argentina. VRM is a fellowship holder from ANPCyT. EGF, LGN, GAE, and OEP are research fellows of CONICET. PAMW is a research fellow of CICPBA, Argentina.

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Authors and Affiliations

  1. Centro de Química Inorgánica (CEQUINOR-CONICET-CICPBA-UNLP), 120 N° 1465, La Plata, Argentina

    Valeria R. Martínez, Luciana G. Naso, Evelina G. Ferrer & Patricia A. M. Williams

  2. Laboratorio de Investigaciones Bioquímicas, Facultad de Medicina, UNNE, Moreno, 1240, Corrientes, Argentina

    María V. Aguirre & Juan S. Todaro

  3. Departamento de Física, Facultad de Ciencias Exactas, Universidad Nacional de La Plata y IFLP (CONICET, CCT La Plata), C.C. 67, 1900, La Plata, Argentina

    Oscar E. Piro & Gustavo A. Echeverría

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  1. Valeria R. Martínez
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Correspondence to Patricia A. M. Williams.

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Supplementary Information Available. Tables of fractional coordinates and equivalent isotropic displacement parameters of the non-H atoms (Table S3), full bond distances and angles (Table S4), atomic anisotropic displacement parameters (Table S5), hydrogen atoms positions (Table S6), and H bond distances and angles (Table S7). Crystallographic structural data have been deposited at the Cambridge Crystallographic Data Centre (CCDC). Any request to the Cambridge Crystallographic Data Centre for this material should quote the full literature citation and the reference number CCDC 1458978. Fig. S1 (Time variation of the electronic absorption spectra of the zinc complex in 96 % EtOH (5 × 10−5 mol/L), room temperature). Fig. S2 (Morphologic changes of A549 cells double stained with AO/EtBr).

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Martínez, V.R., Aguirre, M.V., Todaro, J.S. et al. Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases. Biol Trace Elem Res 186, 413–429 (2018). https://doi.org/10.1007/s12011-018-1334-x

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