ArticleProceedings of the National Academy of Sciences of the United States of America2020
The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 175 citations in OpenAlex.
- A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis.Nature chemical biology · 2026Article
- Novel RNA polymerase I and cyclin-dependent kinase combination therapy for the treatment of aggressive acute myeloid leukemia.Leukemia · 2026Article
- JP-1302 inhibits RNA polymerase I transcription and induces nucleolar stress in cancer cell lines.Cell death discovery · 2026Article
- RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability.The EMBO journal · 2026Article
- G-quadruplex DNA reprograms the photochemistry of CX-5461 toward radical-driven anticancer activity.Nucleic acids research · 2026Article
- G-quadruplex structures as regulators of cellular processes and drivers of genome instability in cancer.Critical reviews in biochemistry and molecular biology · 2026Review
- The Nucleolus in Human Disease: Ribosome Biogenesis, Nucleolar Surveillance, and Therapeutic Opportunities.Biomolecules · 2026Review
- DNA damaging properties of G-quadruplex ligand QN-302 are potentiated by the DNA repair inhibitor Olaparib and mitigated by the molecular helicase PhpC.Genome biology · 2026Article
- CX-5461 and doxorubicin activate a shared DNA damage-associated transcriptional response in human cardiomyocytes.G3 (Bethesda, Md.) · 2026Article
- Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.Molecular cell · 2026Review
- Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.Apoptosis : an international journal on programmed cell death · 2026Review
- TFEB confers resistance against the chemotherapeutic agent CX-5461.Autophagy reports · 2026Article
- Ribosome biogenesis as a potential therapeutic target in KRAS mutant colorectal cancer.Nature communications · 2025Article
- How DNA secondary structures drive replication fork instability.DNA repair · 2025Review
- Targeting RNA polymerase I to boost natural killer cell anticancer activity in multiple myeloma.Cell death & disease · 2025Article
- Dual RNA Polymerase I Inhibition with CX-5461 and BMH-21 Synergizes in Breast Cancer by Activating p53-Dependent Stress.bioRxiv : the preprint server for biology · 2025Article
- Fibrillarin-mediated ribosomal RNA maturation is a novel therapeutic vulnerability in triple-negative breast cancer.Breast cancer research : BCR · 2025Article
- NPM1 mislocalization mediated by RNA Pol I inhibition alters chromatin landscape.bioRxiv : the preprint server for biology · 2025Article
- Hypertranscription of rDNA Responsible for Nucleolar Remodelling is a Doorman for Acquiring Pluripotency.Cell proliferation · 2025Article
- Reply to: The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells.medRxiv : the preprint server for health sciences · 2025Article
43 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.
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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.