Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases
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, t...
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| Veröffentlicht in: | Biological trace element research 2018-12, Vol.186 (2), p.413-429 |
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| description | 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 μM 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 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 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 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 ZnSO
4
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 |
| doi_str_mv | 10.1007/s12011-018-1334-x |
| format | Article |
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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 μM 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 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 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 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 ZnSO
4
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</description><identifier>ISSN: 0163-4984</identifier><identifier>EISSN: 1559-0720</identifier><identifier>DOI: 10.1007/s12011-018-1334-x</identifier><identifier>PMID: 29651733</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>A549 Cells ; Acid phosphatase ; Acid Phosphatase - metabolism ; Activation ; Alkaline phosphatase ; Alkaline Phosphatase - metabolism ; Angiotensin II Type 1 Receptor Blockers - chemistry ; Angiotensin II Type 1 Receptor Blockers - pharmacology ; Apoptosis ; Apoptosis - drug effects ; BAX protein ; bcl-2-Associated X Protein - metabolism ; Bcl-x protein ; bcl-X Protein - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Biotechnology ; Cancer ; Caspase ; Caspase 3 - metabolism ; Caspase-3 ; Cell death ; Cells ; Coordination Complexes - chemistry ; Coordination Complexes - pharmacology ; Crystal structure ; Cytotoxicity ; Depletion ; DNA nucleotidylexotransferase ; Fibroblasts ; Glutathione - metabolism ; Heavy metals ; Human behavior ; Humans ; Interactions ; Life Sciences ; Losartan - chemistry ; Losartan - pharmacology ; Lung cancer ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Lungs ; Necrosis ; Nutrition ; Oncology ; Phosphatase ; Powder ; Proteins ; Ratios ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Solutions ; X-ray diffraction ; Zinc ; Zinc - chemistry ; Zinc - pharmacology ; Zinc compounds</subject><ispartof>Biological trace element research, 2018-12, Vol.186 (2), p.413-429</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2018</rights><rights>Biological Trace Element Research is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-2dd16c2e594ca57f58c52072bb2197f4e945deece499b10cfd34ef3c8351a2153</citedby><cites>FETCH-LOGICAL-c415t-2dd16c2e594ca57f58c52072bb2197f4e945deece499b10cfd34ef3c8351a2153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12011-018-1334-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12011-018-1334-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29651733$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martínez, Valeria R.</creatorcontrib><creatorcontrib>Aguirre, María V.</creatorcontrib><creatorcontrib>Todaro, Juan S.</creatorcontrib><creatorcontrib>Piro, Oscar E.</creatorcontrib><creatorcontrib>Echeverría, Gustavo A.</creatorcontrib><creatorcontrib>Naso, Luciana G.</creatorcontrib><creatorcontrib>Ferrer, Evelina G.</creatorcontrib><creatorcontrib>Williams, Patricia A. M.</creatorcontrib><title>Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases</title><title>Biological trace element research</title><addtitle>Biol Trace Elem Res</addtitle><addtitle>Biol Trace Elem Res</addtitle><description>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 μM 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 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 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 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 ZnSO
4
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</description><subject>A549 Cells</subject><subject>Acid phosphatase</subject><subject>Acid Phosphatase - metabolism</subject><subject>Activation</subject><subject>Alkaline phosphatase</subject><subject>Alkaline Phosphatase - metabolism</subject><subject>Angiotensin II Type 1 Receptor Blockers - chemistry</subject><subject>Angiotensin II Type 1 Receptor Blockers - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>BAX protein</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Bcl-x protein</subject><subject>bcl-X Protein - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Caspase</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase-3</subject><subject>Cell death</subject><subject>Cells</subject><subject>Coordination Complexes - chemistry</subject><subject>Coordination Complexes - pharmacology</subject><subject>Crystal structure</subject><subject>Cytotoxicity</subject><subject>Depletion</subject><subject>DNA nucleotidylexotransferase</subject><subject>Fibroblasts</subject><subject>Glutathione - metabolism</subject><subject>Heavy metals</subject><subject>Human behavior</subject><subject>Humans</subject><subject>Interactions</subject><subject>Life Sciences</subject><subject>Losartan - chemistry</subject><subject>Losartan - pharmacology</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Lungs</subject><subject>Necrosis</subject><subject>Nutrition</subject><subject>Oncology</subject><subject>Phosphatase</subject><subject>Powder</subject><subject>Proteins</subject><subject>Ratios</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Solutions</subject><subject>X-ray diffraction</subject><subject>Zinc</subject><subject>Zinc - chemistry</subject><subject>Zinc - pharmacology</subject><subject>Zinc compounds</subject><issn>0163-4984</issn><issn>1559-0720</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kctuEzEYhS1ERUPhAdggS2zYTOvfl0y8HEUFKkWiUsuGjeV47MRlYg-2p5cn4XVxmhYkJFa-nO8c-9dB6B2QUyCkPctACUBDYNEAY7y5f4FmIIRsSEvJSzQjMGcNlwt-jF7nfEMItFSyV-iYyrmAlrEZ-nURik3aFB8Djg5_D_jOly1exaxT0eEUd1W71c96xZMP2RvcjXEssdTdld8EPfiwwZe6bO_0A_YBr6Z6XupgbMJLOwwZ69Djc-esKRnXsG74sTfZx_vO-B5fbmMet7robPMbdOT0kO3bp_UEfft0fr380qy-fr5YdqvGcBCloX0Pc0OtkNxo0TqxMILW6ddrCrJ13EouemuN5VKugRjXM24dMwsmQFMQ7AR9POSOKf6cbC5q57Op_9XBxikrSqhgAIyQin74B72JU6qTP1KcijlhUCk4UCbFnJN1akx-p9ODAqL2ralDa6q2pvatqfvqef-UPK13tv_jeK6pAvQA5CqFjU1_n_5_6m-hgKN1</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Martínez, Valeria R.</creator><creator>Aguirre, María V.</creator><creator>Todaro, Juan S.</creator><creator>Piro, Oscar E.</creator><creator>Echeverría, Gustavo A.</creator><creator>Naso, Luciana G.</creator><creator>Ferrer, Evelina G.</creator><creator>Williams, Patricia A. 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Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases</title><author>Martínez, Valeria R. ; Aguirre, María V. ; Todaro, Juan S. ; Piro, Oscar E. ; Echeverría, Gustavo A. ; Naso, Luciana G. ; Ferrer, Evelina G. ; Williams, Patricia A. M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-2dd16c2e594ca57f58c52072bb2197f4e945deece499b10cfd34ef3c8351a2153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>A549 Cells</topic><topic>Acid phosphatase</topic><topic>Acid Phosphatase - metabolism</topic><topic>Activation</topic><topic>Alkaline phosphatase</topic><topic>Alkaline Phosphatase - metabolism</topic><topic>Angiotensin II Type 1 Receptor Blockers - chemistry</topic><topic>Angiotensin II Type 1 Receptor Blockers - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>BAX protein</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>Bcl-x protein</topic><topic>bcl-X Protein - metabolism</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Caspase</topic><topic>Caspase 3 - metabolism</topic><topic>Caspase-3</topic><topic>Cell death</topic><topic>Cells</topic><topic>Coordination Complexes - chemistry</topic><topic>Coordination Complexes - pharmacology</topic><topic>Crystal structure</topic><topic>Cytotoxicity</topic><topic>Depletion</topic><topic>DNA nucleotidylexotransferase</topic><topic>Fibroblasts</topic><topic>Glutathione - metabolism</topic><topic>Heavy metals</topic><topic>Human behavior</topic><topic>Humans</topic><topic>Interactions</topic><topic>Life Sciences</topic><topic>Losartan - chemistry</topic><topic>Losartan - pharmacology</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Lungs</topic><topic>Necrosis</topic><topic>Nutrition</topic><topic>Oncology</topic><topic>Phosphatase</topic><topic>Powder</topic><topic>Proteins</topic><topic>Ratios</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Solutions</topic><topic>X-ray diffraction</topic><topic>Zinc</topic><topic>Zinc - chemistry</topic><topic>Zinc - pharmacology</topic><topic>Zinc compounds</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martínez, Valeria R.</creatorcontrib><creatorcontrib>Aguirre, María V.</creatorcontrib><creatorcontrib>Todaro, Juan S.</creatorcontrib><creatorcontrib>Piro, Oscar E.</creatorcontrib><creatorcontrib>Echeverría, Gustavo A.</creatorcontrib><creatorcontrib>Naso, Luciana G.</creatorcontrib><creatorcontrib>Ferrer, Evelina G.</creatorcontrib><creatorcontrib>Williams, Patricia A. 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M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases</atitle><jtitle>Biological trace element research</jtitle><stitle>Biol Trace Elem Res</stitle><addtitle>Biol Trace Elem Res</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>186</volume><issue>2</issue><spage>413</spage><epage>429</epage><pages>413-429</pages><issn>0163-4984</issn><eissn>1559-0720</eissn><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
].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 μM 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 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 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 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 ZnSO
4
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</abstract><cop>New York</cop><pub>Springer US</pub><pmid>29651733</pmid><doi>10.1007/s12011-018-1334-x</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0163-4984 |
| ispartof | Biological trace element research, 2018-12, Vol.186 (2), p.413-429 |
| issn | 0163-4984 1559-0720 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2025311300 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | A549 Cells Acid phosphatase Acid Phosphatase - metabolism Activation Alkaline phosphatase Alkaline Phosphatase - metabolism Angiotensin II Type 1 Receptor Blockers - chemistry Angiotensin II Type 1 Receptor Blockers - pharmacology Apoptosis Apoptosis - drug effects BAX protein bcl-2-Associated X Protein - metabolism Bcl-x protein bcl-X Protein - metabolism Biochemistry Biomedical and Life Sciences Biotechnology Cancer Caspase Caspase 3 - metabolism Caspase-3 Cell death Cells Coordination Complexes - chemistry Coordination Complexes - pharmacology Crystal structure Cytotoxicity Depletion DNA nucleotidylexotransferase Fibroblasts Glutathione - metabolism Heavy metals Human behavior Humans Interactions Life Sciences Losartan - chemistry Losartan - pharmacology Lung cancer Lung Neoplasms - metabolism Lung Neoplasms - pathology Lungs Necrosis Nutrition Oncology Phosphatase Powder Proteins Ratios Reactive oxygen species Reactive Oxygen Species - metabolism Signal transduction Signal Transduction - drug effects Signaling Solutions X-ray diffraction Zinc Zinc - chemistry Zinc - pharmacology Zinc compounds |
| title | Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T23%3A12%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Interaction%20of%20Zn%20with%20Losartan.%20Activation%20of%20Intrinsic%20Apoptotic%20Signaling%20Pathway%20in%20Lung%20Cancer%20Cells%20and%20Effects%20on%20Alkaline%20and%20Acid%20Phosphatases&rft.jtitle=Biological%20trace%20element%20research&rft.au=Mart%C3%ADnez,%20Valeria%20R.&rft.date=2018-12-01&rft.volume=186&rft.issue=2&rft.spage=413&rft.epage=429&rft.pages=413-429&rft.issn=0163-4984&rft.eissn=1559-0720&rft_id=info:doi/10.1007/s12011-018-1334-x&rft_dat=%3Cproquest_cross%3E2024256031%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2024256031&rft_id=info:pmid/29651733&rfr_iscdi=true |