ArticleProceedings of the National Academy of Sciences of the United States of America2020
Uncoupling DNA damage from chromatin damage to detoxify doxorubicin.
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 92 papers.
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Who cites it
92 citing papers in PubMed, 167 citations in OpenAlex.
- Initial preclinical investigation of aclarubicin treatment in primary cutaneous T-cell lymphoma cells.JID innovations : skin science from molecules to population health · 2026Article
- Complete Pathway Refactoring and Combinatorial Biosynthesis of Anthracyclines for Modulation of Histone Eviction and DNA Damage Bioactivities.Angewandte Chemie (International ed. in English) · 2026Article
- Article
- Reconstructing EBV reactivation and DNA damage response kinetics in morphologic pseudotime.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Targeting Activated Pathways in Doxorubicin-Resistant TNBC Alters Signaling, Survival and EMT: A Double-Edged Sword.International journal of molecular sciences · 2026Article
- A simplified co-culture reveals altered cardiotoxic responses to doxorubicin in hPSC-derived cardiomyocytes in the presence of endothelial cells.Stem cell reports · 2026Article
- A triple combination strategy for nasopharyngeal carcinoma: Aptamer-guided liposomal chemotherapy, engineered NK cells, and Fc-enhanced PD-L1 antibody therapy.Acta pharmaceutica Sinica. B · 2026Article
- Determining Preclinical Safety of Aclarubicin in Pediatric Malignancies.Pediatric blood & cancer · 2026Article
- Retinoic Acid and Calcitriol Protect Mouse Primordial Follicles from Cyclophosphamide Treatment-Induced Apoptosis.Antioxidants (Basel, Switzerland) · 2026Article
- Potent immune-dependent anticancer effects of the non-cardiotoxic anthracycline aclarubicin.Oncoimmunology · 2025Review
- Anthracyclines attenuate Nrf1-dependent proteolytic pathways and potentiate proteasome inhibitor cytotoxicity.Molecular biology of the cell · 2025Article
- Targeting the 3D genome by anthracyclines for chemotherapeutic effects.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Reconstructing EBV reactivation and DNA damage response kinetics in morphologic pseudotime.bioRxiv : the preprint server for biology · 2025Article
- Anthracyclines induce global changes in cardiomyocyte chromatin accessibility that overlap with cardiovascular disease loci.PLoS genetics · 2025Article
- Manipulating anthracyclines for deeper tissue penetration and implications for glycolytic tissues.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Daunorubicin and its hydroxy metabolite in cardiomyocytes: insights into cellular kinetics, toxicity, DNA damage, and dexrazoxane-induced cardioprotection.Archives of toxicology · 2025Article
- Irinotecan alleviates chemoresistance to anthracyclines through the inhibition of AARS1-mediated BLM lactylation and homologous recombination repair.Signal transduction and targeted therapy · 2025Article
- Application of Biological Modifiers to a Multiplexed, Human Cell-Based DNA Damage Assay Provides Mechanistic Information on Genotoxicity and Molecular Targets.Environmental and molecular mutagenesis · 2025Article
- Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection.Nature communications · 2025Article
- Nuclear AGO2 supports influenza A virus replication through type-I interferon regulation.Nucleic acids research · 2025Article
32 more citing papers are in PubMed but not listed here.
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Authors and funding
27 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.
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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.