PMID- 29651733
OWN - NLM
STAT- MEDLINE
DCOM- 20190211
LR  - 20190215
IS  - 1559-0720 (Electronic)
IS  - 0163-4984 (Linking)
VI  - 186
IP  - 2
DP  - 2018 Dec
TI  - Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling 
      Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases.
PG  - 413-429
LID - 10.1007/s12011-018-1334-x [doi]
AB  - 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)].3H(2)O (ZnLos) complex has been obtained. The interactions with 
      phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up 
      to 500 muM concentration: a decrease of the acid phosphatase (AcP) associated with 
      an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO(4) 
      showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations 
      higher than 75 muM 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 ZnSO(4), 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 muM, 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 ZnSO(4) 
      at concentrations higher than 200 muM 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.
FAU - Martinez, Valeria R
AU  - Martinez VR
AD  - Centro de Quimica Inorganica (CEQUINOR-CONICET-CICPBA-UNLP), 120 N degrees  1465, La 
      Plata, Argentina.
FAU - Aguirre, Maria V
AU  - Aguirre MV
AD  - Laboratorio de Investigaciones Bioquimicas, Facultad de Medicina, UNNE, Moreno, 
      1240, Corrientes, Argentina.
FAU - Todaro, Juan S
AU  - Todaro JS
AD  - Laboratorio de Investigaciones Bioquimicas, Facultad de Medicina, UNNE, Moreno, 
      1240, Corrientes, Argentina.
FAU - Piro, Oscar E
AU  - Piro OE
AD  - Departamento de Fisica, Facultad de Ciencias Exactas, Universidad Nacional de La 
      Plata y IFLP (CONICET, CCT La Plata), C.C. 67, 1900, La Plata, Argentina.
FAU - Echeverria, Gustavo A
AU  - Echeverria GA
AD  - Departamento de Fisica, Facultad de Ciencias Exactas, Universidad Nacional de La 
      Plata y IFLP (CONICET, CCT La Plata), C.C. 67, 1900, La Plata, Argentina.
FAU - Naso, Luciana G
AU  - Naso LG
AD  - Centro de Quimica Inorganica (CEQUINOR-CONICET-CICPBA-UNLP), 120 N degrees  1465, La 
      Plata, Argentina.
FAU - Ferrer, Evelina G
AU  - Ferrer EG
AD  - Centro de Quimica Inorganica (CEQUINOR-CONICET-CICPBA-UNLP), 120 N degrees  1465, La 
      Plata, Argentina.
FAU - Williams, Patricia A M
AU  - Williams PAM
AD  - Centro de Quimica Inorganica (CEQUINOR-CONICET-CICPBA-UNLP), 120 N degrees  1465, La 
      Plata, Argentina. williams@quimica.unlp.edu.ar.
LA  - eng
PT  - Journal Article
DEP - 20180412
PL  - United States
TA  - Biol Trace Elem Res
JT  - Biological trace element research
JID - 7911509
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Coordination Complexes)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 0 (bcl-X Protein)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
RN  - EC 3.1.3.2 (Acid Phosphatase)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - GAN16C9B8O (Glutathione)
RN  - J41CSQ7QDS (Zinc)
RN  - JMS50MPO89 (Losartan)
SB  - IM
MH  - A549 Cells
MH  - Acid Phosphatase/*metabolism
MH  - Alkaline Phosphatase/*metabolism
MH  - Angiotensin II Type 1 Receptor Blockers/chemistry/pharmacology
MH  - Apoptosis/*drug effects
MH  - Caspase 3/metabolism
MH  - Coordination Complexes/chemistry/*pharmacology
MH  - Glutathione/metabolism
MH  - Humans
MH  - Losartan/chemistry/*pharmacology
MH  - Lung Neoplasms/metabolism/pathology
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
MH  - Zinc/chemistry/*pharmacology
MH  - bcl-2-Associated X Protein/metabolism
MH  - bcl-X Protein/metabolism
OTO - NOTNLM
OT  - Anticancer mechanism
OT  - Enzymatic inhibition
OT  - Losartan
OT  - Zinc coordination
EDAT- 2018/04/14 06:00
MHDA- 2019/02/12 06:00
CRDT- 2018/04/14 06:00
PHST- 2018/02/14 00:00 [received]
PHST- 2018/04/03 00:00 [accepted]
PHST- 2018/04/14 06:00 [pubmed]
PHST- 2019/02/12 06:00 [medline]
PHST- 2018/04/14 06:00 [entrez]
AID - 10.1007/s12011-018-1334-x [pii]
AID - 10.1007/s12011-018-1334-x [doi]
PST - ppublish
SO  - Biol Trace Elem Res. 2018 Dec;186(2):413-429. doi: 10.1007/s12011-018-1334-x. 
      Epub 2018 Apr 12.