Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia

Publication type:
Journal article
Metadata:
Autoren
  • Sami Hamdoun
  • Philipp Jung
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000395911100001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3389/fphar.2017.00110
Externe Identifier
  • Clarivate Analytics Document Solution ID: EN3LX
  • PubMed Identifier: 28344555
ISSN
1663-9812
Zeitschrift
FRONTIERS IN PHARMACOLOGY
Schlüsselwörter
  • chemotherapy
  • pharmacogenomics
  • drug resistance
  • transcription factors
  • oxidative stress
Artikelnummer
ARTN 110
Datum der Veröffentlichung
2017
Status
Published
Titel
Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
Sub types
  • Article
Ausgabe der Zeitschrift
8

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Sami Hamdoun
  • Philipp Jung
  • Thomas Efferth
DOI
10.3389/fphar.2017.00110
eISSN
1663-9812
Zeitschrift
Frontiers in Pharmacology
Online publication date
2017
Status
Published online
Herausgeber
Frontiers Media SA
Herausgeber URL
http://dx.doi.org/10.3389/fphar.2017.00110
Datum der Datenerfassung
2019
Titel
Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
Ausgabe der Zeitschrift
8

Data source: Crossref

Abstract
Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (<i>p</i> = 8.66 × 10<sup>5</sup>). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz, Germany.
Autoren
DOI
10.3389/fphar.2017.00110
eISSN
1663-9812
Externe Identifier
  • PubMed Identifier: 28344555
  • PubMed Central ID: PMC5344920
Open access
true
ISSN
1663-9812
Zeitschrift
Frontiers in pharmacology
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2017
Open access status
Open Access
Paginierung
110
Datum der Veröffentlichung
2017
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2017
Titel
Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
8

Files

https://www.frontiersin.org/articles/10.3389/fphar.2017.00110/pdf https://europepmc.org/articles/PMC5344920?pdf=render

Data source: Europe PubMed Central

Abstract
Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.
Date of acceptance
2017
Autoren
  • Sami Hamdoun
  • Philipp Jung
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/28344555
DOI
10.3389/fphar.2017.00110
Externe Identifier
  • PubMed Central ID: PMC5344920
ISSN
1663-9812
Zeitschrift
Front Pharmacol
Schlüsselwörter
  • chemotherapy
  • drug resistance
  • oxidative stress
  • pharmacogenomics
  • transcription factors
Sprache
eng
Country
Switzerland
Paginierung
110
Datum der Veröffentlichung
2017
Status
Published online
Titel
Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
8

Data source: PubMed

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