ArticleBiochemistry2014
Etoposide quinone is a covalent poison of human topoisomerase IIβ.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 45 citations in OpenAlex.
- Article
- Myeloperoxidase inhibition protects bone marrow mononuclear cells from DNA damage induced by the TOP2 poison anti-cancer drug etoposide.FEBS open bio · 2024Article
- Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Cell survival after DNA damage in the comet assay.Archives of toxicology · 2021Article
- Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play.Translational oncology · 2021Review
- Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity.Xenobiotica; the fate of foreign compounds in biological systems · 2021Article
- Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons.Cell chemical biology · 2021Article
- Review
- Article
- Dirigent Proteins Guide Asymmetric Heterocoupling for the Synthesis of Complex Natural Product Analogues.Journal of the American Chemical Society · 2021Article
- Bioflavonoids cause DNA double-strand breaks and chromosomal translocations through topoisomerase II-dependent and -independent mechanisms.Mutation research. Genetic toxicology and environmental mutagenesis · 2020Article
- Isobaric tags for relative and absolute quantitation-based quantitative proteomic analysis of X-linked inhibitor of apoptosis and H2AX in etoposide-induced renal cell carcinoma apoptosis.Chinese medical journal · 2019Article
- Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II.Journal of chemical information and modeling · 2019Article
- Formation and biological targets of botanical o-quinones.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2018Review
- Synthesis and molecular docking studies of some novel Schiff bases incorporating 6-butylquinolinedione moiety as potential topoisomerase IIβ inhibitors.Royal Society open science · 2018Article
- Azoreductases in drug metabolism.British journal of pharmacology · 2017Review
- Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy.Molecular pharmacology · 2017Article
- Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.Science (New York, N.Y.) · 2016Article
- Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase IIα Isoform.The Journal of pharmacology and experimental therapeutics · 2016Article
- IS METABOLIC ACTIVATION OF TOPOISOMERASE II POISONS IMPORTANT IN THE MECHANISM OF CYTOTOXICITY?Journal of drug metabolism & toxicology · 2015Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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.
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