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.
Highlights
Drugs targeting DNA topoisomerase II (TOP2 poisons) are important, effective, and widely used anticancer agents, but they are associated with short- and long-term toxic side effects, including neutropenia and rare but life-threatening therapy-related acute myeloid leukemia (t-AML) (Allan and Travis, 2005; Leone et al, 2010; Cowell and Austin, 2012)
We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced DNA topoisomerase IIb (TOP2A) and DNA topoisomerase IIb (TOP2B)-DNA covalent complexes in cells, which are converted to DNA double-strand breaks
The observation that SA pretreatment, which reduces MPO-mediated etoposide phenoxy radical production, partially suppressed etoposide-induced topoisomerase II covalent complex (TOP2-CC) formation in MPO-expressing NB4 cells supports the conclusion that oxidative metabolism of etoposide plays a role in TOP2mediated DNA damage in vivo
Summary
Drugs targeting DNA topoisomerase II (TOP2 poisons) are important, effective, and widely used anticancer agents, but they are associated with short- and long-term toxic side effects, including neutropenia and rare but life-threatening therapy-related acute myeloid leukemia (t-AML) (Allan and Travis, 2005; Leone et al, 2010; Cowell and Austin, 2012). Therapy related leukemias, especially those appearing after exposure to TOP2 poisons often contain recurrent chromosome translocations, including t(15,17)(PML-RARA), t(8,21)(AML-ETO), and 11q23 rearrangements involving the MLL gene (Rowley and Olney, 2002; Cowell and Austin, 2012). These genetic lesions disrupt blood cell development and play a pivotal role in the development of the disease. There are two vertebrate TOP2 paralogues, TOP2A and TOP2B; TOP2 poisons such as etoposide affect both paralogues, but recent evidence points to a greater role for TOP2B in generating the genotoxic damage associated with TOP2 poisons (Azarova et al, 2007; Cowell et al, 2012; Smith et al, 2014a)
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