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DNA topoisomerases and their poisoning by anticancer and antibacterial drugs

Yves Pommier1, Elisabetta Leo, HongLiang Zhang

  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA. pommier@nih.gov

Chemistry & Biology
|June 11, 2010
PubMed

Insights

DNA topoisomerases are crucial drug targets for cancer and bacterial infections. Inhibitors like camptothecins and quinolones work by trapping enzyme-DNA complexes, offering therapeutic potential.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • DNA topoisomerases are essential enzymes involved in DNA replication, transcription, and repair.
  • These enzymes are validated targets for numerous anticancer and antibacterial drugs.
  • Existing drugs target both eukaryotic (Top1, Top2) and bacterial (gyrase, Topo IV) topoisomerases.

Purpose of the Study:

  • To review the molecular and biochemical properties of topoisomerases.
  • To discuss the characteristics of various topoisomerase inhibitors.
  • To elucidate the mechanism of action of topoisomerase poisons.

Main Methods:

  • Literature review of topoisomerase research.
  • Analysis of biochemical data on topoisomerase-inhibitor interactions.
  • Examination of clinical development of novel topoisomerase-targeting agents.

Main Results:

  • Eukaryotic type IB topoisomerases (Top1) are targeted by camptothecins and novel noncamptothecins (e.g., indenoisoquinolines).
  • Human type IIA topoisomerases (Top2alpha, Top2beta) are targeted by etoposide, anthracyclines, and mitoxantrone.
  • Bacterial type II topoisomerases are targeted by quinolones and aminocoumarin antibiotics.

Conclusions:

  • Topoisomerase poisons function by interfacial inhibition, stabilizing the covalent topoisomerase-cleavage complex.
  • Understanding these mechanisms is key to developing new antimicrobial and anticancer therapies.
  • Targeting topoisomerases remains a vital strategy in drug discovery.

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