ArticleThe Journal of biological chemistry2008
NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 104 citations in OpenAlex.
- Analysis of gene expression changes upon topobexin treatment and TOP2B-knockout in hiPSC-derived cardiomyocytes.Biology open · 2026Article
- Structural Mechanisms of Topoisomerase-Targeting Drugs.Annual review of biochemistry · 2025Review
- Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection.Nature communications · 2025Article
- Palindromic carbazole derivatives: unveiling their antiproliferative effect via topoisomerase II catalytic inhibition and apoptosis induction.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Simulation- and AI-directed optimization of 4,6-substituted 1,3,5-triazin-2(1Computational and structural biotechnology journal · 2024Article
- Bioinformatic Analysis of Topoisomerase IIα Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues.International journal of molecular sciences · 2024Article
- Use of CRISPR/Cas9 with Homology-Directed Repair to Gene-Edit Topoisomerase IIThe Journal of pharmacology and experimental therapeutics · 2024Article
- Naturally mutagenic sequence diversity in a human type II topoisomerase.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- DNA fragility at theOpen biology · 2023Review
- Exploration of the Role of the C-Terminal Domain of Human DNA Topoisomerase IIα in Catalytic Activity.ACS omega · 2021Article
- Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy.Molecular biology reports · 2021Review
- Review
- Substituted 4,5'-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα.Journal of chemical information and modeling · 2020Article
- Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells.Molecular biology reports · 2020Article
- The DNA topoisomerase II inhibitor amsacrine as a novel candidate adjuvant in a model of glaucoma filtration surgery.Scientific reports · 2019Article
- Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations.Molecular pharmacology · 2019Article
- Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives.International journal of molecular sciences · 2018Review
- TOP2B: The First Thirty Years.International journal of molecular sciences · 2018Review
- Synthesis, Bacteriostatic and Anticancer Activity of Novel Phenanthridines Structurally Similar to Benzo[c]phenanthridine Alkaloids.Molecules (Basel, Switzerland) · 2018Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Topoisomerase II (Top2) is a ubiquitous nuclear enzyme that relieves torsional stress in chromosomal DNA during various cellular processes. Agents that target Top2, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective anticancer drugs used in the clinic. Mammalian cells possess two genetically distinct Top2 isoforms, both of which are the target of these agents. Top2alpha is essential for cell proliferation and is highly expressed in vigorously growing cells, whereas Top2beta is nonessential for growth and has recently been implicated in treatment-associated secondary malignancies, highlighting the validity of a Top2alpha-specific drug for future cancer treatment; however, no such agent has been hitherto reported. Here we show that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2alpha and not Top2beta in vivo. Unlike other Top2 inhibitors, NK314 induces Top2-DNA complexes and double-strand breaks (DSBs) in an alpha isoform-specific manner. Heterozygous disruption of the human TOP2alpha gene confers increased NK314 resistance, whereas TOP2beta homozygous knock-out cells display increased NK314 sensitivity, indicating that the alpha isoform is the cellular target. We further show that the absence of Top2beta does not alleviate NK314 hypersensitivity of cells deficient in non-homologous end-joining, a critical pathway for repairing Top2-mediated DSBs. Our results indicate that NK314 acts as a Top2alpha-specific poison in mammalian cells, with excellent potential as an efficacious and safe chemotherapeutic agent. We also suggest that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents.
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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.