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Gmeiner et al. Cancer Drug Resist 2021;4:758-61 Cancer
DOI: 10.20517/cdr.2021.65
Drug Resistance

Editorial Open Access

Targeting DNA topoisomerases: past & future

1
William H. Gmeiner , Robert C. A. M. van Waardenburg 2
1
Department of Cancer Biology Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
2
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Correspondence to: Dr. William H. Gmeiner, Department of Cancer Biology Wake Forest School of Medicine, Medical Center
Blvd, Winston-Salem, NC 27157, USA. E-mail: bgmeiner@wakehealth.edu; Dr. Robert C. A. M. van Waardenburg, Department of
Pharmacology and Toxicology, University of Alabama at Birmingham, 155 Volker Hall, 1670 University Boulevard, Birmingham,
AL 35294-0019, USA. E-mail: rvanwaar@uab.edu

How to cite this article: Gmeiner WH, van Waardenburg RCAM. Targeting DNA topoisomerases: past & future. Cancer Drug
Resist 2021;4:758-61. https://dx.doi.org/10.20517/cdr.2021.65

Received: 12 Jul 2021 Accepted: 19 Jul 2021 First online: 21 Jul 2021

Academic Editor: Godefridus J. Peters Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them
especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.
DNA topoisomerases resolve topological problems associated with DNA replication and other essential
cellular processes involving DNA, such as transcription and recombination . As such, they are important
[1]
targets for anti-cancer therapeutics. Further, understanding of topoisomerase biology is important for
unraveling the mechanistic basis for resistance to many widely used anti-cancer drugs, such as doxorubicin,
etoposide, and topotecan, for which DNA topoisomerases are established targets. Interestingly, several
drugs that are not considered to directly target topoisomerase enzymes, such as the nucleoside analogs 5-FU
and AraC, and those in development such as the polymeric fluoropyrimidine CF10 , also affect the
[2]
function of topoisomerases.

DNA topoisomerase II (Top2) enzymes reduce DNA superhelicity by introducing a transient DNA double
strand break to facilitate transport of another region of duplex DNA through the break. The Top2α isoform
is only expressed during G2-M phase, and it is a major target for anticancer drugs, including etoposide and
doxorubicin that interfere in a re-ligation step of the Top2α catalytic cycle, stabilizing the Top2α cleavage
complex (Top2cc), and converting the enzyme into a cellular poison. The activity of DNA Top2α is
modulated by multiple post-translational modifications (PTMs) including phosphorylation, acetylation,

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
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