Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-car-boxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000710782200003&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.bcp.2021.114788
eISSN
1873-2968
Externe Identifier
  • Clarivate Analytics Document Solution ID: WM0JS
  • PubMed Identifier: 34582772
ISSN
0006-2952
Zeitschrift
BIOCHEMICAL PHARMACOLOGY
Schlüsselwörter
  • Cancer
  • Apoptosis
  • Drug development
  • ER stress
  • Multidrug resistance
  • PERK/eIF2 alpha/ATF4 pathway
Artikelnummer
ARTN 114788
Datum der Veröffentlichung
2021
Status
Published
Titel
Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-car-boxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway
Sub types
  • Article
Ausgabe der Zeitschrift
193

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
DOI
10.1016/j.bcp.2021.114788
ISSN
0006-2952
Zeitschrift
Biochemical Pharmacology
Sprache
en
Artikelnummer
114788
Paginierung
114788 - 114788
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.bcp.2021.114788
Datum der Datenerfassung
2022
Titel
Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway
Ausgabe der Zeitschrift
193

Data source: Crossref

Abstract
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G<sub>2</sub>M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.1016/j.bcp.2021.114788
eISSN
1873-2968
Externe Identifier
  • PubMed Identifier: 34582772
Funding acknowledgements
  • China Scholarship Council:
Open access
false
ISSN
0006-2952
Zeitschrift
Biochemical pharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Oxazines
  • Xanthenes
  • eIF-2 Kinase
  • Eukaryotic Initiation Factor-2
  • Antineoplastic Agents
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Gene Deletion
  • Molecular Structure
  • Drug Resistance, Neoplasm
  • Activating Transcription Factor 4
  • Gene Regulatory Networks
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Paginierung
114788
Datum der Veröffentlichung
2021
Status
Published
Datum der Datenerfassung
2021
Titel
Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
193

Data source: Europe PubMed Central

Abstract
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G2M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
Date of acceptance
2021
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/34582772
DOI
10.1016/j.bcp.2021.114788
eISSN
1873-2968
Zeitschrift
Biochem Pharmacol
Schlüsselwörter
  • Apoptosis
  • Cancer
  • Drug development
  • ER stress
  • Multidrug resistance
  • PERK/eIF2α/ATF4 pathway
  • Activating Transcription Factor 4
  • Antineoplastic Agents
  • Cell Line, Tumor
  • Cell Survival
  • Drug Resistance, Neoplasm
  • Eukaryotic Initiation Factor-2
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Molecular Structure
  • Oxazines
  • Xanthenes
  • eIF-2 Kinase
Sprache
eng
Country
England
Paginierung
114788
PII
S0006-2952(21)00404-4
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Titel
Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
193

Data source: PubMed

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