The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning
| Autor: | Stephen J. Elledge, Kady A. Dennis, Haider Inam, Peter M. Bruno, Connor J. Moore, John Sheehe, Justin R. Pritchard, Mengrou Lu, Michael T. Hemann |
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| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Lymphoma Cell Survival DNA damage Cell Antineoplastic Agents Drug action Sensitivity and Specificity Gene Expression Regulation Enzymologic Cell Line Tumor medicine RNA polymerase I Humans Doxorubicin Benzothiazoles Naphthyridines Poly-ADP-Ribose Binding Proteins Multidisciplinary Dose-Response Relationship Drug biology Mechanism (biology) Topoisomerase Biological Sciences Gene Expression Regulation Neoplastic DNA Topoisomerases Type II medicine.anatomical_structure biology.protein Cancer research RNA Interference medicine.drug |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1921649117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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