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Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

Lookup NU author(s): Dr Mandeep Atwal, Emma Lishman-Walker, Professor Caroline AustinORCiD, Dr Ian CowellORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells andtransforms the topoisomerase II poisons etoposide and mitoxantrone to chemical forms that havealtered DNA damaging properties. TOP2 poisons are valuable and widely used anti-cancer drugs, butthey are associated with the occurrence of secondary acute myeloid leukemias. These factors haveled to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2poison-mediated genotoxic damage, and therefore reduce the rate of therapy-related leukemia. Weshow here that myeloperoxidase activity leads to elevated accumulation of etoposide- andmitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted toDNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater forTOP2B than for TOP2A. This is a significant finding as TOP2B has been linked to genetic damageassociated with leukemic transformation, including etoposide-induced chromosomal breaks at theMLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced duringchemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2BDNAcomplexes and DSB formation. Together these results support targeting MPO activity to reducegenetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recentdevelopment of novel specific MPO inhibitors for use in inflammatory diseases involving neutrophilinfiltration.

Publication metadata

Author(s): Atwal M, Lishman EL, Austin CA, Cowell IG

Publication type: Article

Publication status: Published

Journal: Molecular Pharmacology

Year: 2017

Volume: 91

Issue: 1

Pages: 49-57

Online publication date: 01/01/2017

Acceptance date: 08/11/2016

Date deposited: 14/12/2016

ISSN (electronic): 1521-0111

Publisher: ASPET Journals

URL: https://doi.org/10.1124/mol.116.106054

DOI: 10.1124/mol.116.106054

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