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

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 c...

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Autores principales: Hamdoun, Sami, Jung, Philipp, Efferth, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344920/
https://www.ncbi.nlm.nih.gov/pubmed/28344555
http://dx.doi.org/10.3389/fphar.2017.00110
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author Hamdoun, Sami
Jung, Philipp
Efferth, Thomas
author_facet Hamdoun, Sami
Jung, Philipp
Efferth, Thomas
author_sort Hamdoun, Sami
collection PubMed
description 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 × 10(5)). 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.
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spelling pubmed-53449202017-03-24 Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia Hamdoun, Sami Jung, Philipp Efferth, Thomas Front Pharmacol Pharmacology 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 × 10(5)). 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. Frontiers Media S.A. 2017-03-10 /pmc/articles/PMC5344920/ /pubmed/28344555 http://dx.doi.org/10.3389/fphar.2017.00110 Text en Copyright © 2017 Hamdoun, Jung and Efferth. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Hamdoun, Sami
Jung, Philipp
Efferth, Thomas
Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
title Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
title_full Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
title_fullStr Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
title_full_unstemmed Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
title_short Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia
title_sort drug repurposing of the anthelmintic niclosamide to treat multidrug-resistant leukemia
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344920/
https://www.ncbi.nlm.nih.gov/pubmed/28344555
http://dx.doi.org/10.3389/fphar.2017.00110
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