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DNA topoisomerase-targeting chemotherapeutics: what’s new?

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Abstract

To resolve the topological problems that threaten the function and structural integrity of nuclear and mitochondrial genomes and RNA molecules, human cells encode six different DNA topoisomerases including type IB enzymes (TOP1 and TOP1mt), type IIA enzymes (TOP2α and TOP2β) and type IA enzymes (TOP3α and TOP3β). DNA entanglements and the supercoiling of DNA molecules are regulated by topoisomerases through the introduction of transient enzyme-linked DNA breaks. The covalent topoisomerase–DNA complexes are the cellular targets of a diverse group of cancer chemotherapeutics, which reversibly stabilize these reaction intermediates. Here we review the structure–function and catalytic mechanisms of each family of eukaryotic DNA topoisomerases and the topoisomerase-targeting agents currently approved for patient therapy or in clinical trials, and highlight novel developments and challenges in the clinical development of these agents.

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Acknowledgements

We would like to thank the past and current Bjornsti and van Waardenburg lab members, and colleagues for inspiring discussions that contribute to the continued development of the DNA topoisomerases field. Our apologies to colleagues whose work we did not mention, due to space limitations. RCAMvW greatly appreciates the financial support from the Department of Pharmacology and Toxicology, UAB ACS-IRG Junior Faculty Development Grant (ACS-IRG-60-001-53), the UAB Comprehensive Cancer Center Faculty Development Grant, and DOD OCRP pilot award W81XWH-15-1-0198. M-AB acknowledges the support from the National Institutes of Health and, along with RCAMvW, support from the Alabama Drug Discovery Alliance and the Cancer Center Core Support Grant P30CA013148.

Funding

This study was in part funded by American Cancer Society UAB ACS-IRG Junior Faculty Development Grant (ACS-IRG-60-001-53), Department of Defense OCRP pilot award W81XWH-15-1-0198 to RCAMvW, and the National Institutes of Health Cancer Center Core Support Grant (P30CA013148) to RCAMvW and M-AB.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 155 Volker Hall, 1720 2nd Ave. S., Birmingham, AL, 35294-0019, USA

    Selma M. Cuya, Mary-Ann Bjornsti & Robert C.A.M. van Waardenburg

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  1. Selma M. Cuya
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  2. Mary-Ann Bjornsti
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  3. Robert C.A.M. van Waardenburg
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Correspondence to Robert C.A.M. van Waardenburg.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Cuya, S.M., Bjornsti, MA. & van Waardenburg, R.C. DNA topoisomerase-targeting chemotherapeutics: what’s new?. Cancer Chemother Pharmacol 80, 1–14 (2017). https://doi.org/10.1007/s00280-017-3334-5

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  • DOI: https://doi.org/10.1007/s00280-017-3334-5

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