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

Abstract

Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double-strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration.

Topical film prepared with Rhus verniciflua extract‐loaded pullulan hydrogel for atopic dermatitis treatment

“…Serum MPO activity was determined by using an MPO detection kit as previously described . Immediately after the induction of anesthesia, blood was harvested from all rats ( n = 5 per group).…”

“…Serum MPO activity was determined by using an MPO detection kit as previously described. 38 Immediately after the induction of anesthesia, blood was harvested from all rats (n = 5 per group). Blood samples were transferred to evacuated tubes containing heparin solution as anticoagulant and then centrifuged at 3000g for 10 min to yield the serum.…”

TOP2B: The First Thirty Years

“…Using an isoform-specific microscopy based immunoassay (trapped in agarose DNA immunostaining or TARDIS assay) [ 73 , 74 ] to detect TOP2-DNA covalent complexes, we showed that etoposide induces complexes with both TOP2 isoforms, as does mAMSA and mitoxantrone [ 75 , 76 , 77 ]. The half-lives of the complexes in cells can be determined using the TARDIS assay.…”

Pixantrone: novel mode of action and clinical readouts

“…Data for DOX are from Patel & Kaufman 2012 [10], Sawyer 2013 [12] and Zhang 2012 [46]. Data for MITOX are from Atwal et al 2017 [47], Faulds et al 1991 [16] and Damiani et al 2016 [48]. © Les Laboratoires Servier, 2018 (published with permission) anthracycline activity (tumor cell killing) have been proposed, but interaction with DNA-topoisomerase II complex is thought to be the primary mechanism for inducing cell death [11].…”

“…Mitoxantrone is not activated via reduction (unlike doxorubicin), but by oxidative metabolism (e.g. by myeloperoxidase [47] or cytochrome P450 [48] to free radical intermediates (quinone, quinonediimine) [48]. Mitoxantrone appears to have a weaker capacity to enter redox cycling generating ROS and it has been proposed that it induces energy imbalance [48], although further research is required to confirm this.…”