Lookup NU author(s): Dr Mandeep Atwal,
Professor Caroline Austin,
Dr Ian Cowell
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Atwal M, Lishman EL, Austin CA, Cowell IG
Publication type: Article
Publication status: Published
Journal: Molecular Pharmacology
Online publication date: 01/01/2017
Acceptance date: 08/11/2016
Date deposited: 14/12/2016
ISSN (electronic): 1521-0111
Publisher: ASPET Journals
Altmetrics provided by Altmetric