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

Frontiers in Pharmacology
Sami HamdounThomas Efferth

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...Continue Reading

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Citations

Dec 18, 2019·Journal of Cellular Physiology·Sowjanya ThatikondaChandraiah Godugu
Dec 31, 2019·Seminars in Cancer Biology·Thomas Efferth, Franz Oesch
Dec 15, 2020·Investigational New Drugs·Mohamed E M SaeedThomas Efferth
Jul 3, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jelena DinićIvanka Tsakovska
Mar 30, 2021·Frontiers in Oncology·Miguel Olivas-AguirreOxana Dobrovinskaya
Jun 1, 2021·ACS Biomaterials Science & Engineering·Maedeh Koohi Moftakhari EsfahaniEmad L Izake

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Methods Mentioned

BETA
Fluorescence
microscale thermophoresis
Assay
flow cytometry

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