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The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy Matias-Barrios, Victor M.; Dong, Xuesen

Abstract

DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.

Item Metadata

Title
The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy
Creator
Matias-Barrios, Victor M.; Dong, Xuesen
Contributor
Vancouver Prostate Centre
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2023-01-09
Description
DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.
Subject
DNA topoisomerase II; topoisomerase inhibitors; synthetic lethality; DNA damage repair; DNA repair inhibitors; Myc; EZH2
Genre
Article
Type
Text
Language
eng
Date Available
2025-01-30
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0447874
URI
http://hdl.handle.net/2429/90239
Affiliation
Medicine, Faculty of; Urologic Sciences, Department of
Citation
Pharmaceuticals 16 (1): 94 (2023)
Publisher DOI
10.3390/ph16010094
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0