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Etoposide quinone is a covalent poison of human topoisomerase IIβ.
- Source :
-
Biochemistry [Biochemistry] 2014 May 20; Vol. 53 (19), pp. 3229-36. Date of Electronic Publication: 2014 May 02. - Publication Year :
- 2014
-
Abstract
- Etoposide is a topoisomerase II poison that is utilized to treat a broad spectrum of human cancers. Despite its wide clinical use, 2-3% of patients treated with etoposide eventually develop treatment-related acute myeloid leukemias (t-AMLs) characterized by rearrangements of the MLL gene. The molecular basis underlying the development of these t-AMLs is not well understood; however, previous studies have implicated etoposide metabolites (i.e., etoposide quinone) and topoisomerase IIβ in the leukemogenic process. Although interactions between etoposide quinone and topoisomerase IIα have been characterized, the effects of the drug metabolite on the activity of human topoisomerase IIβ have not been reported. Thus, we examined the ability of etoposide quinone to poison human topoisomerase IIβ. The quinone induced ~4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ~2 times greater against topoisomerase IIβ than it was against topoisomerase IIα, and the drug reacted ~2-4 times faster with the β isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA. These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIβ.
- Subjects :
- DNA chemistry
DNA metabolism
Humans
Topoisomerase II Inhibitors metabolism
DNA Topoisomerases, Type II chemistry
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins chemistry
Etoposide chemistry
Leukemia ethnology
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins chemistry
Quinones chemistry
Topoisomerase II Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 53
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24766193
- Full Text :
- https://doi.org/10.1021/bi500421q