DNA Topoisomerases and Their Poisoning by Anticancer and Antibacterial Drugs

By Yves Pommier, Elisabetta Leo, Hongliang Zhang, Christophe H. Marchand. Chemistry and Biology, 2010

1,790 citations recorded by the source corpus.

DNA topoisomerases are the targets of important anticancer and antibacterial drugs. Camptothecins and novel noncamptothecins in clinical development (indenoisoquinolines and ARC-111) target eukaryotic type IB topoisomerases (Top1), whereas human type IIA topoisomerases (Top2α and Top2β) are the targets of the widely used anticancer agents etoposide, anthracyclines (doxorubicin, daunorubicin), and mitoxantrone. Bacterial type II topoisomerases (gyrase and Topo IV) are the targets of quinolones and aminocoumarin antibiotics. This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors. We also discuss the common mechanism of action of topoisomerase poisons by interfacial inhibition and trapping of topoisomerase cleavage complexes.

Subfields: Molecular Biology, Oncology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/7c2a68be418453d68465e4f74846743a7a90dd94

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Citations in the corpus

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics (2022, background): “Etoposide creates a ternary complex with DNA and the topoisomeraseeII complex, preventing the latter’s binding to the DNA strands, while in doing so, it causes damage to DNA strands.(120) Cancer cells depend on this enzyme more than healthy cells, as they divide more quickly; therefore, it causes de”
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse (2016, background): “Doxo intercalates into DNA and prevents topoisomerase II from resealing the DNA double strand break, which the enzyme creates to relieve torsional stress (16).”
cGAS is essential for cellular senescence (2017, background): “The topoisomerase inhibitor etoposide is a cytotoxic anticancer agent that induces DNA damage and cellular senescence (35, 36).”
Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics (2015, background): “Afterward, the two ends are ligated together by TopoII, relieving the tangle and allowing cell division to proceed (116, 117).”
Doxorubicin—An Agent with Multiple Mechanisms of Anticancer Activity (2023, background): “Low dosages (<1 μM) of DOX are believed to capture covalently bound topoisomerase II at DNA ds-breaking sites and inhibit DNA relegation [68,69].”
Doxorubicin, DNA torsion, and chromatin dynamics (2013, neutral): “This process results in the release of torsional stress formed during biological processes such as DNA replication and transcription (discussed below) [12].”
The DNA damage response and cancer therapy (2012, background): “Topoisomerase inhibitors, such as irinotecan (a topoisomerase I inhibitor) and etoposide (a topoisomerase II inhibitor), could be regarded as the first generation of DDR 'targeted' agent”
Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action (2016, methodology): “For the TOP1 inhibitors, including the widely used camptothecin derivatives, irinotecan and topotecan (10, 51, 60), synergy with PARP inhibitors is solely due to PARP catalytic inhibition and does not require PARP trapping.”