ArticleThe Journal of pharmacology and experimental therapeutics2016
Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase IIα Isoform.
Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 64 citations in OpenAlex.
- Histidinol dehydrogenase (HisD): a critical regulator ofMicrobiology spectrum · 2026Article
- Mechanism-informed identification of FDA-approved topoisomerase inhibitors disrupting SARS-CoV-2 nucleocapsid-RNA interactions.BMC chemistry · 2025Article
- Anticancer drugs targeting topoisomerase II for antifungal treatment.Scientific reports · 2025Article
- Article
- Use of CRISPR/Cas9 with Homology-Directed Repair to Gene-Edit Topoisomerase IIThe Journal of pharmacology and experimental therapeutics · 2024Article
- Interactions of pixantrone with apurinic/apyrimidinic sites in DNA.microPublication biology · 2024Article
- Pixantrone Sensitizes Gram-Negative Pathogens to Rifampin.Microbiology spectrum · 2022Article
- Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance).The oncologist · 2022Article
- Current Opinion on Pixantrone in the Treatment of Non-Hodgkin B-Cell Lymphoma.Therapeutics and clinical risk management · 2021Review
- Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma.Oncology letters · 2020Article
- Pixantrone demonstrates significant in vitro activity against multiple myeloma and plasma cell leukemia.Annals of hematology · 2019Review
- Pixantrone anticancer drug as a DNA ligand: Depicting the mechanism of action at single molecule level.The European physical journal. E, Soft matter · 2019Article
- Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations.Molecular pharmacology · 2019Article
- Pixantrone beyond monotherapy: a review.Annals of hematology · 2019Review
- Topoisomerases and cancer chemotherapy: recent advances and unanswered questions.F1000Research · 2019Review
- Role of Endothelium in Doxorubicin-Induced Cardiomyopathy.JACC. Basic to translational science · 2018Review
- Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives.International journal of molecular sciences · 2018Review
- Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway.Oncology letters · 2018Article
- Synthesis and antiproliferative activity of derivatives of the phyllanthusmin class of arylnaphthalene lignan lactones.Bioorganic & medicinal chemistry · 2018Article
- Pixantrone, a new anticancer drug with the same old cardiac problems? An in vitro study with differentiated and non-differentiated H9c2 cells.Interdisciplinary toxicology · 2018Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Pixantrone is a new noncardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones, such as doxorubicin and mitoxantrone. Pixantrone is approved in the European Union for the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanism(s) of its anticancer activity and its relative lack of cardiotoxicity. Pixantrone targeted DNA topoisomerase IIα as evidenced by its ability to inhibit kinetoplast DNA decatenation; to produce linear double-strand DNA in a pBR322 DNA cleavage assay; to produce DNA double-strand breaks in a cellular phospho-histone γH2AX assay; to form covalent topoisomerase II-DNA complexes in a cellular immunodetection of complex of enzyme-to-DNA assay; and to display cross-resistance in etoposide-resistant K562 cells. Pixantrone produced semiquinone free radicals in an enzymatic reducing system, although not in a cellular system, most likely due to low cellular uptake. Pixantrone was 10- to 12-fold less damaging to neonatal rat myocytes than doxorubicin or mitoxantrone, as measured by lactate dehydrogenase release. Three factors potentially contribute to the reduced cardiotoxicity of pixantrone. First, its lack of binding to iron(III) makes it unable to induce iron-based oxidative stress. Second, its low cellular uptake may limit its ability to produce semiquinone free radicals and redox cycle. Finally, because the β isoform of topoisomerase II predominates in postmitotic cardiomyocytes, and pixantrone is demonstrated in this study to be selective for topoisomerase IIα in stabilizing enzyme-DNA covalent complexes, the attenuated cardiotoxicity of this agent may also be due to its selectivity for targeting topoisomerase IIα over topoisomerase IIβ.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.