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Lookup NU author(s): Dr Mandeep Atwal, Rebecca Swan, Ka Lee, Dr David Lee, Professor Lyle Armstrong, Dr Ian CowellORCiD, Professor Caroline AustinORCiD
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TOP2 poisons are effective cytotoxic anticancer agents that stabilise the normally transient TOP2-DNA covalent complexes formed during the enzyme reaction cycle. These drugs include etoposide, mitoxantrone and the anthracyclines, doxorubicin and epirubicin. Anthracyclines also exert cell-killing activity via TOP2-independent mechanisms including DNA adduct formation, redox activity and lipid peroxidation. Here we show that anthracyclines and another intercalating TOP2 poison mitoxantrone stabilise TOP2-DNA covalent complexes less efficiently than etoposide and at higher concentrations they suppress the formation of TOP2-DNA covalent complexes, thus behaving as TOP2 poisons at low concentration and inhibitors at high concentration. We employed iPSC-derived human cardiomyocytes as a model to study anthracycline induced damage in cardiac cells. We demonstrated for the first-time using immunofluorescence the presence of TOP2B as the only TOP2 isoform in iPSC derived cardiomyocytes. In these cells etoposide robustly induced TOP2B-covalent complexes, but we could not detect doxorubicin-induced TOP2- DNA complexes, and doxorubicin supressed etoposide-induced TOP2-DNA complexes. In vitro, etoposide-stabilised DNA cleavage was attenuated by doxorubicin, epirubicin or mitoxantrone. Clinical use of anthracyclines is associated with cardiotoxicity. The observations in this study have potentially important clinical consequences regarding the effectiveness of anticancer treatment regimens when TOP2 targeting drugs are used in combination. These observations suggest that inhibition of TOP2B activity rather than DNA damage resulting from TOP2 poisoning may play a role in doxorubicin cardiotoxicity.
Author(s): Atwal M, Swan RL, Rowe C, Lee KC, Lee DC, Armstrong L, Cowell IG, Austin CA
Publication type: Article
Publication status: Published
Journal: Molecular Pharmacology
Year: 2019
Volume: 96
Issue: 4
Pages: 475-484
Print publication date: 01/10/2019
Online publication date: 09/08/2019
Acceptance date: 02/08/2019
Date deposited: 08/08/2019
ISSN (print): 0026-895X
ISSN (electronic): 1521-0111
Publisher: American Society for Pharmacology and Experimental Therapeutics
URL: https://doi.org/10.1124/mol.119.117259
DOI: 10.1124/mol.119.117259
PubMed id: 31399497
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