Toggle Main Menu Toggle Search

Open Access padlockePrints

Intercalating TOP2 poisons attenuate topoisomerase action at higher concentrations

Lookup NU author(s): Dr Mandeep Atwal, Rebecca Swan, Ka Lee, Dr David Lee, Professor Lyle Armstrong, Dr Ian Cowell, Professor Caroline Austin

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

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.


Publication metadata

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


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share