Targeting DNA topoisomerase II in cancer chemotherapy

Key Points

  • Topoisomerase II (TOP2) is the target of several important classes of anticancer drugs, including the epipodophyllotoxin etoposide and the anthracycline doxorubicin.

  • Most clinically active drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex. Therefore, the principal action of the TOP2-targeting drugs that are currently used is to generate enzyme-mediated DNA damage.

  • A recent structure of the breakage reunion domain of TOP2 bound to DNA has been determined. This structure is likely to be useful for understanding the protein determinants of the action of drugs targeting TOP2. A drug–protein–DNA ternary complex would be valuable but has not yet been determined.

  • TOP2-mediated DNA damage is repaired by multiple pathways. This DNA damage includes DNA strand breaks and proteins that are covalently bound to DNA. Repair of TOP2-mediated damage requires double-strand break repair pathways and other pathways that are specific for the removal of protein–DNA adducts.

  • Sensitivity to TOP2-targeting drugs depends in part on the levels of TOP2. Cells overexpressing TOP2 are hypersensitive to TOP2 poisons and cells expressing low levels of TOP2 are drug resistant. TOP2A is frequently co-amplified with ERBB2, which can lead to the development of tumours with increased levels of TOP2α.

  • An important side effect of targeting TOP2 with TOP2 poisons is the formation of secondary malignancies that arise from drug-induced translocations. TOP2β might be the TOP2 isoform that is most responsible for the secondary malignancies caused by TOP2-targeting drugs.

  • Anthracycline use is limited by cardiotoxicity. Although the mechanism of the cardiotoxicity is poorly understood, recent results suggest that anthracyclines that target TOP2β might contribute to cardiotoxicity. There might be considerable benefit to developing TOP2-targeting drugs that are specific for the TOP2α isoform.

  • Catalytic inhibition of TOP2 could also be a useful anticancer strategy. New compounds are being developed to test this possibility.

Abstract

Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.

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Figure 1: Mechanisms of inhibiting topoisomerase II.
Figure 2: Structure of topoisomerase II bound to DNA.
Figure 3: Pathways for the repair of topoisomerase II-mediated DNA damage.

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Acknowledgements

The author thanks J. Berger, University of California, Berkeley, USA, who kindly provided figures and also provided useful discussions, and also Y. Pommier, National Cancer Institute, Bethesda, for encouragement. Work in the author's laboratory is supported by grants from the National Cancer Institute (CA82313 and CA21765) and the American Lebanese Syrian Associated Charities (ALSAC).

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DATABASES

National Cancer Institute Drug Dictionary

aclarubicin

amonafide

bortezomib

doxorubicin

etoposide

ICRF-159

mAMSA

mitoxantrone

teniposide

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Glossary

Bisdioxopiperazines

A class of small molecules, including ICRF-159, ICRF-187 and MST-16, that inhibit the catalytic activity of TOP2 and do not stabilize the TOP2 cleaved complex. Bisdioxopiperazines are the most commonly used catalytic inhibitors of type II topoisomerases.

TOPRIM domain

A conserved domain found in topoisomerases, primases and other DNA metabolic enzymes. The TOPRIM domain adopts a Rossman fold, and is involved in divalent cation binding.

MRN complex

A protein complex consisting of MRE11, RAD50 and nibrin (NBN), which is required for checkpoint signalling and double strand break repair. In yeast, the NBN component is replaced by a protein called Xrs2 and the yeast complex is termed the MRX complex. The yeast complex is required for removing Spo11 from DNA during meiotic recombination.

TOP2β isozyme

In lower eukaryotes for example, yeast, insects and vertebrates such as Xenopus laevis – there is a single Top2 isoform. Mammals have two TOP2 isoforms termed α and β. The α isoform is preferentially expressed in proliferating cells and is essential for all growing cells. The β isoform is expressed in quiescent cells and is required for viability in mice.

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Nitiss, J. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9, 338–350 (2009). https://doi.org/10.1038/nrc2607

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