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Review
. 2023 Jan 9;16(1):94.
doi: 10.3390/ph16010094.

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Victor M Matias-Barrios  1   2 , Xuesen Dong  1
Affiliations
Review

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Victor M Matias-Barrios et al. Pharmaceuticals (Basel). .

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.

Keywords: DNA damage repair; DNA repair inhibitors; DNA topoisomerase II; EZH2; Myc; synthetic lethality; topoisomerase inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Catalytic cycle of Top2. Relaxed/tangled DNA dynamics process: (1) the enzyme binds to double-strand DNA; (2) the DNA cleavage reaction requires Mg2+; (3) two molecules of ATP bind to the N-terminal domain; (4) ATP hydrolysis provides the energy for DNA passage; (5) DNA repair/re-ligation; and (6) dissociation of DNA–Top2 complex after the second ATP hydrolysis. Top2 is then ready to start a new cycle of enzymatic activity. The figure was created on biorender.com.
Figure 2
Figure 2
DNA damage response and repair pathways. Several DSB repair mechanisms are available based on the phase of the cell cycle and the existence of homology sequences in the DNA strands. The DNA repair mechanism could undergo the HR or the NHEJ pathway according to the cell cycle stage at the moment of the lesion and the acquired mutations in the cell. The figure was created on biorender.com.
Figure 3
Figure 3
Synthetic lethality of Top2 inhibition in combination with DDR inhibitors. Top2 inhibition generates DNA damage during double-strand breaks or DNA replication stress. These perturbations to the cell can be abolished by DNA damage repair pathways, thus allowing the cell to survive. However, inhibiting the proteins involved in the repair mechanism can increase the efficacy of Top2 inhibitors by producing synthetic lethality. The figure was created on biorender.com.
Figure 4
Figure 4
Top2 inhibition synthetic lethality with Myc/EZH2. (A) Top2–EZH2–Myc relationship with AR-dependent and CRPC tumor cell survival signaling pathways. (B) Top2–EZH2–Myc relationship with NEPC survival signaling pathways. The figure was created on biorender.com.
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