The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning
Open accessAbstract
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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Recent genome-wide investigations underscore that these effects are not confined to promotors, but are rather observed across the genome.
“Recent genome-wide investigations underscore that these effects are not confined to promotors, but are rather observed across the genome (68–70).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [68]
The Significance and Data sections describe CX-5461’s mechanism and analyses across cell lines, not where effects occur within the genome. Searches for promoters and effects across the genome found no passage establishing that the effects extend beyond promoters. (LLM, conf=0.74)
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“Our study, together with very recent reports (Bruno et al., 2020; Olivieri et al., 2020), indicates that cytotoxic effects induced by CX-5461 and PDS mainly rely on the formation of DNA breaks through a TOP2-dependent mechanism, arguing for the presence in these molecules of structural determinants that may block TOP2…”
BackgroundResultG-quadruplex-mediated genomic instability drives SNVs in cancer
Richl, T., Kuper, J., & Kisker, C. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae098 · Cited by 20 · see citing works
- Authors
- Bruno, P. M., Lu, M., Dennis, K. A., Inam, H., Moore, C. J., Sheehe, J., Elledge, S. J., Hemann, M. T., & Pritchard, J. R.
- Affiliations
- Brigham and Women's Hospital (US)
- Pennsylvania State University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Elledge, Stephen J.
- Hemann, Michael T.
- Pritchard, Justin R.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-02-10
- Volume
- 117
- Issue
- 8
- Pages
- 4053-4060
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7049172
- OpenAlex
- W3004754093
- Cited by
- 175
- References
- 1
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 25 · 2023: 31 · 2022: 31 · 2021: 25 · 2020: 21
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- HHS | NIH | National Cancer Institute (CA233477-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- CX-5461, RNA polymerase I inhibition, cytotoxicity mechanism, G-quadruplex formation, DNA damage, doxorubicin resistance, acquired drug resistance, lymphoma cells, hematologic malignancies, drug repurposing
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, Antineoplastic Agents, Cell Survival, DNA Topoisomerases, Type II, Dose-Response Relationship, Drug, Doxorubicin, Humans, Lymphoma, Naphthyridines, Sensitivity and Specificity, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, RNA Interference, Cell Line, Tumor, Benzothiazoles
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