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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

  • Valeria R. Martínez
  • María V. Aguirre
  • Juan S. Todaro
  • Oscar E. Piro
  • Gustavo A. Echeverría
  • Luciana G. Naso
  • Evelina G. Ferrer
  • Patricia A. M. Williams
Article
  • 51 Downloads

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.

Graphical abstract

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

Keywords

Losartan Zinc coordination Enzymatic inhibition Anticancer mechanism 

Notes

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.

Supplementary material

12011_2018_1334_MOESM1_ESM.docx (622 kb)
ESM 1 (DOCX 622 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Valeria R. Martínez
    • 1
  • María V. Aguirre
    • 2
  • Juan S. Todaro
    • 2
  • Oscar E. Piro
    • 3
  • Gustavo A. Echeverría
    • 3
  • Luciana G. Naso
    • 1
  • Evelina G. Ferrer
    • 1
  • Patricia A. M. Williams
    • 1
  1. 1.Centro de Química Inorgánica (CEQUINOR-CONICET-CICPBA-UNLP)La PlataArgentina
  2. 2.Laboratorio de Investigaciones Bioquímicas, Facultad de Medicina, UNNECorrientesArgentina
  3. 3.Departamento de Física, Facultad de Ciencias ExactasUniversidad Nacional de La Plata y IFLP (CONICET, CCT La Plata)La PlataArgentina

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